Compositions and methods for treating hepatic porphyria using glycine transport inhibitors

Abstract

This embodiment is directed to a method of using a glycine transporter inhibitor, such as a GlyT1 inhibitor, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, or a pharmaceutical composition thereof, for preventing or treating hepatic porphyria and related syndromes. In certain embodiments, the disclosure provides a method of treating hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of a GlyT1 inhibitor or salts thereof.

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 347,415, filed May 31, 2022. The specification of the foregoing application is hereby incorporated by reference in its entirety.

[0002] Field Embodiments disclosed herein are directed to methods and uses for preventing or treating hepatic porphyria using glycine transporter inhibitors, such as, but not limited to, GlyT1 inhibitors or pharmaceutically acceptable salts, hydrates, prodrugs thereof, or pharmaceutical compositions thereof.

Background Art

[0003] Background Porphyria is a family of disorders resulting from a deficiency in the activity of specific enzymes in the heme biosynthetic pathway, also referred to herein as the porphyrin pathway. Each porphyria is classified as hepatic or erythropoietic based on the organ system in which heme precursors are overproduced. They are also classified as acute or non-acute based on their clinical presentation. Deficiencies in the enzymes of the porphyrin pathway lead to insufficient heme production and the accumulation of porphyrin precursors (e.g., ALA and PBG) and porphyrins that are toxic to tissues at high concentrations.

[0004] Acute hepatic porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and aminolevulinate dehydratase deficiency porphyria (ADP), and often lead to severe abdominal, psychopathological, neurological, or cardiovascular symptoms. Each acute hepatic porphyria results from a genetic defect leading to a deficiency of one of the enzymes in the heme synthesis pathway in the liver. Porphyria cutanea tarda (PCT) is a non-acute hepatic porphyria, and its patients often present with herpes, blisters, milia, and hirsutism on the cheeks, temples, and eyebrows. In addition, there is a rare homozygous recessive form of PCT known as hepatoerythropoietic porphyria (HEP).

[0005] In acute porphyrias (e.g., AIP, VP, HCP, and ADP), each enzyme deficiency can be neurotoxic and can lead to the appearance of an acute attack, resulting in the hepatic production and accumulation of one or more substances (e.g., porphyrins and / or porphyrin precursors, such as ALA and / or PBG). If not properly treated, quadriplegia, respiratory dysfunction, and death can result. These genetic disorders are rare and often difficult to diagnose. Approximately one in 10,000 Europeans has a mutation in one of the genes that cause AIP, VP, or HCP. However, most (80 - 90%) of the identified genetic carriers remain asymptomatic, while others experience one or several acute attacks throughout their lives.

[0006] Current therapies for acute neurological attacks include intravenous administration of hemin (Panhematin®, Lundbeck or Normosang®, Orphan Europe), which provides exogenous heme due to negative feedback inhibition of ALAS1, thereby reducing the production of ALA and PBG. Hemin is used, in particular, in women with acute porphyria who experience frequent attacks due to hormonal changes during their menstrual cycle, for treatment during acute attacks and for prevention of attacks. Patients generally respond well, but the effect is slow and typically takes 2 - 4 days or longer to normalize urinary ALA and PBG concentrations. Since intravenous hemin is rapidly metabolized, 3 - 4 infusions are usually required to effectively treat or prevent acute attacks. In addition, repeated infusions can cause iron overload and phlebitis, which can compromise peripheral venous access.

[0007] Givosiran (Givlaari®), a small interfering ribonucleic acid (siRNA) against aminolevulinate synthase 1, is also used to treat patients with acute hepatic porphyria by using RNA interference to target and degrade ALAS1 mRNA in hepatocytes. Suspected risks associated with the use of givosiran include anaphylactic reactions, hepatotoxicity, and nephrotoxicity. For example, 15% of patients in a givosiran clinical trial showed an increase in transaminase (ALT) three times the upper limit of normal. In addition, 15% of patients who received givosiran had kidney-related adverse reactions, including an increase in serum creatinine levels and a decrease in estimated glomerular filtration rate. One ultimate treatment is orthotrophic liver transplantation. Orthotrophic liver transplantation is curative, but this procedure has significant morbidity and mortality, and the availability of liver donors is limited. Accordingly, there is a need for new methods and compositions for treating and / or preventing hepatic porphyria. The methods and uses of glycine transporter inhibitors, such as, but not limited to, GlyT1 inhibitors, described herein, satisfy these needs as well as others.

Summary of the Invention

Means for Solving the Problems

[0008] Summary of the Application In certain embodiments, the present disclosure provides a method of treating hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of GlyT1 inhibitors or salts thereof.

[0009] In certain embodiments, the present disclosure provides a method of preventing, treating, or reducing the rate of progression and / or severity of hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter 1 (GlyT1) inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of GlyT1 inhibitors or salts thereof.

[0010] In certain embodiments, the present disclosure provides a method for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more GlyT1 inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of GlyT1 inhibitors or pharmaceutically acceptable salts thereof. In some embodiments, one or more complications of hepatic porphyria are selected from the group consisting of acute photosensitivity, cutaneous photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte abnormalities, nausea, vomiting, constipation, diarrhea, dysuria, ileus, paresthesia, insomnia, restlessness, agitation, anxiety, delirium, hallucinations, psychosis, seizures, pain associated with neuropathy, muscle paralysis, quadriplegia, decreased respiration, apnea, hyponatremia, tachycardia, hypertension, increased heart rate, increased blood pressure, red urine, dark urine, hepatocellular carcinoma, hypertensive kidney injury, chronic kidney disease, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratosis, blisters, lesions, scarring, deformity, loss of fingernails, loss of fingers, cholestasis, cytolysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, worsening of liver disease, and end-stage liver disease. In some embodiments, the hepatic porphyria is acute hepatic porphyria. In some embodiments, the acute hepatic porphyria is acute intermittent porphyria (AIP). In some embodiments, the acute hepatic porphyria is ALA dehydratase porphyria (ADP). In some embodiments, the acute hepatic porphyria is variegate porphyria (VP). In some embodiments, the acute hepatic porphyria is hereditary coproporphyria (HCP). In some embodiments, the acute hepatic porphyria is harderoporphyria. In some embodiments, the hepatic porphyria is non-acute hepatic porphyria. In some embodiments, the non-acute hepatic porphyria is familial and sporadic late-onset cutaneous porphyria (PCT). In some embodiments, the non-acute hepatic porphyria is myeloporphyria (HEP).In some embodiments, acute photosensitivity is caused by sunlight exposure. In some embodiments, the method increases painless light exposure in a subject. In some embodiments, the method decreases photosensitivity in a subject.

[0011] In certain aspects, the present disclosure provides a method of inhibiting 5-aminolevulinic acid (5-ALA) synthesis in a subject, comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the subject has hepatic porphyria.

[0012] In certain aspects, the present disclosure provides a method of inhibiting coproporphyrin III synthesis in vivo, comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

[0013] In certain aspects, the present disclosure provides a method of inhibiting zinc protoporphyrin IX (ZPPIX) synthesis in a subject, comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the subject has ALA dehydratase porphyria (ADP).

[0014] In certain aspects, the present disclosure provides a method of inhibiting porphobilinogen (PBG) synthesis in vivo, comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.

[0015] In certain embodiments, the present disclosure provides a method of inhibiting 5-aminolevulinic acid (5-ALA) and porphobilinogen (PBG) synthesis in vivo, comprising administering a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, to a subject.

[0016] In certain embodiments, the present disclosure provides a method of inhibiting hydroxymethylbilane (HMB) synthesis in vivo, comprising administering a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, to a subject.

[0017] In certain embodiments, the present disclosure provides a method of inhibiting uroporphyrin III synthesis in vivo, comprising administering a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, to a subject.

[0018] In certain embodiments, the present disclosure provides a method of inhibiting heptacarboxyl-porphyrin synthesis in vivo, comprising administering a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, to a subject.

[0019] In certain embodiments, the present disclosure provides a method of inhibiting isocoproporphyrin synthesis in vivo, comprising administering a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, to a subject.

[0020] In certain embodiments, the disclosure provides a method of inhibiting the synthesis of porphyrin or a porphyrin precursor in vivo, comprising administering a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the porphyrin or porphyrin precursor is selected from the group consisting of 5-ALA; PBG; hydroxymethylbilane; ZPPIX; uroporphyrinogen I; uroporphyrinogen III; heptacarboxyporphyrinogen I; heptacarboxyporphyrinogen III; hexacarboxyporphyrinogen I; hexacarboxyporphyrinogen III; pentacarboxyporphyrinogen I; pentacarboxyporphyrinogen III; coproporphyrinogen I; coproporphyrinogen III; isocoproporphyrin; porphobilinogen; and protoporphyrinogen IX.

[0021] In some embodiments, the accumulation of one or more heme intermediates is inhibited, and the one or more heme intermediates are selected from the group consisting of 5-ALA, coproporphyrin III, zinc protoporphyrin IX (ZPPIX), porphobilinogen, uroporphyrin III, heptacarboxyl-porphyrin, and isocoproporphyrin. In some embodiments, the accumulation of one or more heme intermediates is inhibited, and the one or more heme intermediates are selected from the group consisting of 5-ALA; PBG; hydroxymethylbilane; ZPPIX; uroporphyrinogen I; uroporphyrinogen III; heptacarboxylporphyrinogen I; heptacarboxylporphyrinogen III; hexacarboxylporphyrinogen I; hexacarboxylporphyrinogen III; pentacarboxylporphyrinogen I; pentacarboxylporphyrinogen III; coproporphyrinogen I; coproporphyrinogen III; isocoproporphyrin; porphobilinogen; and protoporphyrinogen IX. In some embodiments, the accumulation of one or more heme intermediates is inhibited in a dose-dependent manner. In some embodiments, the GlyT1 inhibitor demonstrates an EC50 of less than 500 nM. In some embodiments, the GlyT1 inhibitor demonstrates an EC50 of less than 100 nM.

[0022] In some embodiments, the subject has or is at risk of developing hepatic porphyria and suffers from pain (e.g., neuropathic pain, e.g., chronic neuropathic pain) or neuropathy (e.g., progressive neuropathy). In some embodiments, the subject has elevated levels of ALA and / or PBG and suffers from chronic pain. In some embodiments, the subject has a 5-ALA level that is at least 10%, 20%, 30%, 40%, or 50% higher than the 5-ALA level in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has an HMB level that is at least 10%, 20%, 30%, 40%, or 50% higher than the HMB level in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has a coproporphyrin III level that is at least 10%, 20%, 30%, 40%, or 50% higher than the coproporphyrin III level in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has a ZPPIX level that is at least 10%, 20%, 30%, 40%, or 50% higher than the ZPPIX level in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has a porphobilinogen level that is at least 10%, 20%, 30%, 40%, or 50% higher than the porphobilinogen level in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has a uroporphyrin III level that is at least 10%, 20%, 30%, 40%, or 50% higher than the uroporphyrin III level in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has a heptacarboxyl-porphyrin level that is at least 10%, 20%, 30%, 40%, or 50% higher than the heptacarboxyl-porphyrin level in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has an isocoproporphyrin level that is at least 10%, 20%, 30%, 40%, or 50% higher than the isocoproporphyrin level in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the subject's heme level is substantially maintained during treatment.In some embodiments, the treatment reduces the subject's hem level by a decrease of 10% or less (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the administration of the pharmaceutical composition does not cause a substantial reduction in the hem level. In some embodiments, the subject has an increased 5-ALA level. In some embodiments, the subject has an increased 5-ALA level in urine. In some embodiments, the subject has an increased 5-ALA level in plasma. In some embodiments, the subject has an increased HMB level. In some embodiments, the subject has an increased coproporphyrin III level. In some embodiments, the subject has an increased coproporphyrin III level in urine. In some embodiments, the subject has an increased coproporphyrin III level in feces. In some embodiments, the subject has an increased porphobilinogen (PBG) level. In some embodiments, the subject has an increased porphobilinogen (PBG) level in urine. In some embodiments, the subject has a plasma or urine level of 5-ALA or PBG that is higher than a reference value. In some embodiments, the reference value is 2 standard deviations above the average level in samples from healthy individuals. In some embodiments, the subject has a plasma or urine level of 5-ALA or PBG that is higher than or equal to 2, 3, 4, or 5 times the reference upper limit. In some embodiments, the subject has a urine level of PBG that is higher than or equal to 4.8 mmol / mol creatinine. In some embodiments, the subject has a plasma PBG level that is higher than or equal to 0.12 μmol / L. In some embodiments, the subject has a urine PBG level that is higher than or equal to 1.2 mmol / mol creatinine. In some embodiments, the subject has a plasma 5-ALA level that is higher than or equal to 0.12 μmol / L. In some embodiments, the subject has a urine 5-ALA level that is higher than or equal to 3.1 mmol / mol creatinine. In some embodiments, the method reduces the elevated levels of 5-ALA and / or PBG. In some embodiments, the subject has an increased uroporphyrin III level.In some embodiments, the subject has increased uroporphyrin III levels in urine. In some embodiments, the subject has an increased ratio of protoporphyrin to coproporphyrin in feces. In some embodiments, the subject has increased heptacarboxyl-porphyrin levels. In some embodiments, the subject has increased heptacarboxyl-porphyrin levels in urine. In some embodiments, the subject has increased heptacarboxyl-porphyrin levels in feces. In some embodiments, the subject has increased isocoproporphyrin levels. In some embodiments, the subject has increased isocoproporphyrin levels in feces. In some embodiments, the subject has increased ZPPIX levels in red blood cells.

[0023] In some embodiments, the method reduces the 5-ALA level in a subject. In some embodiments, the method reduces the 5-ALA level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the HMB level in a subject. In some embodiments, the method reduces the HMB level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the coproporphyrin III level in a subject. In some embodiments, the method reduces the coproporphyrin III level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the PBG level in a subject. In some embodiments, the method reduces the PBG level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method is effective to reduce the level of 5-ALA and / or PBG. In some embodiments, the level of 5-ALA and / or PBG is reduced such that it falls below a reference value. In some embodiments, the reference value is a reference upper limit. In some embodiments, the method reduces the uroporphyrin III level in a subject. In some embodiments, the method reduces the uroporphyrin III level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).In some embodiments, the method reduces the ratio of protoporphyrin to coproporphyrin in a subject. In some embodiments, the method reduces the ratio of protoporphyrin to coproporphyrin in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the heptacarboxyl-porphyrin level in a subject. In some embodiments, the method reduces the heptacarboxyl-porphyrin level in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the isocoproporphyrin level in a subject. In some embodiments, the method reduces the isocoproporphyrin level in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the ZPPIX level in a subject. In some embodiments, the method reduces the ZPPIX level in a subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%).

[0024] In some embodiments, the plasma porphyrin of interest fluoresces at a peak of 615 nm to 620 nm when irradiated with blue light (e.g., light of 400 - 420 nm). In some embodiments, the plasma porphyrin of interest fluoresces at a peak of 624 nm to 627 nm when irradiated with blue light (e.g., light of 400 - 420 nm). In some embodiments, the skin porphyrin of interest fluoresces at a peak of 615 nm to 620 nm when irradiated with blue light (e.g., light of 400 - 420 nm). In some embodiments, the skin porphyrin of interest fluoresces at a peak of 624 nm to 627 nm when irradiated with blue light (e.g., light of 400 - 420 nm). In some embodiments, the subject has a deficiency in an enzyme selected from the group consisting of ALA - dehydratase; PBG deaminase; uroporphyrinogen III synthase; uroporphyrinogen decarboxylase; coproporphyrinogen oxidase; and protoporphyrinogen oxidase. In some embodiments, the subject has a mutation in a gene selected from the group consisting of ALAD; HMBS; UROS; UROD; CPOX; and PPOX.

[0025] In some embodiments, the GlyT1 inhibitor is administered after an acute attack. In some embodiments, the GlyT1 inhibitor is administered during an acute attack. In some embodiments, the GlyT1 inhibitor is administered during premonitory symptoms. In some embodiments, the premonitory symptoms are characterized by pain (e.g., headache and / or abdominal pain), nausea, psychological symptoms (e.g., anxiety), restlessness and / or insomnia. In some embodiments, the GlyT1 inhibitor is administered prophylactically to prevent an acute attack of hepatic porphyria. In some embodiments, the GlyT1 inhibitor is administered during a particular stage of the menstrual cycle, e.g., during the luteal phase. In some embodiments, the GlyT1 inhibitor restores or prevents a periodic attack of hepatic porphyria. In some embodiments, the periodic attack is associated with exacerbating factors. In some embodiments, the exacerbating factor is a particular stage of the menstrual cycle, e.g., the luteal phase. In some embodiments, the exacerbating factor is the premenstrual period. In some embodiments, the exacerbating factor is exposure to a chemical. In some embodiments, the exacerbating factor is exposure to lead. In some embodiments, the exacerbating factor is selected from the group consisting of drugs, foreign bodies, steroid hormones, smoking, alcohol, decreased intake of calories or carbohydrates, starvation, metabolic stress, and psychological stress. In some embodiments, the method reduces pain or neuropathy. In some embodiments, the method prevents an acute attack of hepatic porphyria. In some embodiments, the method reduces or prevents nerve damage. In some embodiments, the GlyT1 inhibitor is administered prophylactically starting at puberty. In some embodiments, the method further comprises administering to the subject an additional active agent and / or supportive therapy.In some embodiments, additional active agents and / or supportive therapies include sun avoidance, topical sunscreen, skin protection, UVB phototherapy, afamelanotide (Scenesse®), bortezomib, heme infusion, adequate calorie support, gibostirane, RNAi-mediated silencing of various enzymes (e.g., ALA synthase), avoidance of exacerbating factors, 4-aminoquinoline, chloroquine, hydroxychloroquine, phlebotomy, intravenous magnesium, LH-RH agonists, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of the PBGD gene into liver cells by viral vectors), hemodialysis, pharmacological chaperone treatment, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and blood transfusion, and are selected from the group consisting of.

[0026] In certain embodiments, the GlyT1 inhibitor has the formula I [Chemical formula] [wherein Ar is unsubstituted or substituted aryl or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, wherein the substituted aryl group and the substituted heteroaryl group are hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n-(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR 7 R 8 , C(O)R 9 , SO2R 10 and -C(CH3)=NOR 7 and is substituted by one or more substituents selected from the group consisting of or optionally substituted by (C1-C6)-alkyl and is substituted by a 5-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from N and O; R 1 is hydrogen or (C1-C6)-alkyl; R 2is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n-(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or halogen, CH(CH3)-(C3-C7)-cycloalkyl, (CH2) n+1 -C(O)-R 9 、(CH2) n+1 -CN, bicyclo[2.2.1]heptyl, (CH2) n+1 -O-(C1-C6)-alkyl, (CH2) n -heterocycloalkyl, (CH2) n -aryl or (CH2) n -5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen, (CH2) n -5- or 6-membered heteroaryl, wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy; R 3 、R 4 およびR 6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O-(C3-C6)-cycloalkyl; R 5 is NO2, CN, C(O)R 9 or SO2R 10 ; R 7 およびR 8 are each independently hydrogen or (C1-C6)-alkyl; R 9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR 7 R 8 ; R 10 is (C1-C6)-alkyl optionally substituted by halogen, (CH2) n -(C3-C6)-cycloalkyl, (CH2)n -(C3-C6)-alkoxy, (CH2) n -heterocycloalkyl or NR 7 R 8 wherein; n is 0, 1 or 2] a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0027] In certain embodiments, the GlyT1 inhibitor is

Chemical Structure

[0028] In certain embodiments, the GlyT1 inhibitor is of formula II

Chemical Structure

Chemical formula

Chemical formula

[0029] In certain embodiments, the GlyT1 inhibitor is of formula III

Chemical formula

Chemical formula

[0030] In certain embodiments, the GlyT1 inhibitor is of formula IV

Chemical formula

Chemical formula

[0031] In certain embodiments, the GlyT1 inhibitor is of formula V [Chemical] [wherein, n is an integer of 1 to 3; R 1 and R 2 are independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein the aforementioned rings are independently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, mono-substituted amino or di-substituted amino R a , R b or R c is optionally substituted; or R 1 and R 2 when bonded to the same carbon atom, may combine to form cycloalkyl or monocyclic saturated heterocyclyl to provide a spiro ring, wherein the cycloalkyl or monocyclic saturated heterocyclyl is independently selected from alkyl, alkoxy, fluoro, fluoroalkyl, fluoroalkoxy, hydroxy, mono-substituted amino or di-substituted amino R d , R c or R f is optionally substituted; or R 1 and R 2 when bonded to the carbon atoms at the 2- and 5- or 3- and 6-positions of the piperazine ring, may combine to form a -C1-C3- alkylene chain, wherein one of the carbon atoms in the alkylene chain is optionally replaced by -NR-, -O-, -S(O)n- (wherein R is hydrogen or alkyl and n is 0 to 2), and further, one or two hydrogen atoms in the alkylene chain may be optionally substituted by one or two alkyls; R 3 , R 4 and R 5 are independently hydrogen, alkyl, fluoro or fluoroalkyl; Ar 1 and Ar 2 are independently aryl, heteroaryl, cycloalkyl or heterocyclyl, wherein each of the aforementioned rings is R g , R h or Ri which is optionally replaced as necessary, and R g is alkyl, -C=C-R 6 (wherein R 6 is aryl or heteroaryl), halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, mono-substituted amino, di-substituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl or acylamino, and R h and R i are independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, mono-substituted amino, di-substituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, acylamino, aryl, heteroaryl, cycloalkyl or heterocyclyl, where the aromatic or alicyclic ring in R g , R h and R i is independently selected from R j , R k or R lwhich is optionally replaced, provided that the compound of formula V is not 2-(4-benzhydrylpiperazin-1-yl)acetic acid, 2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)acetic acid, 2-((2R,5S)-4-((R)-(4-(1H-tetrazol-5-yl)phenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-yl)acetic acid or 2-((2R,5S)-4-((R)-(4-cyanophenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-yl)acetic acid a compound of formula or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is [Chemical formula] a compound having the formula of or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0032] In certain embodiments, the GlyT1 inhibitor is of formula VI [Chemical formula] [wherein, A represents a group of the general formula N-R1, a group of the general formula N+(O-)R1 or a group of the general formula N+(R’)R1 (wherein, R1 represents a hydrogen atom, or a linear or branched (C1-C7) alkyl group optionally substituted with one or more fluorine atoms, or a (C4-C7) cycloalkyl group, or a (C3-C7) cycloalkyl(C1-C3)alkyl group, or a phenyl(C1-C3)alkyl group optionally substituted with one or two hydroxyl groups or methoxy groups, or a (C2-C4) alkenyl group, or a (C2-C4) alkynyl group; R’ represents a linear or branched (C1-C7) alkyl group); X represents a hydrogen atom, or one or more substituents selected from a halogen atom and trifluoromethyl, linear or branched (C1-C4) alkyl and (C1-C4) alkoxy groups; R2 represents a hydrogen atom, or one or more substituents selected from a halogen atom and trifluoromethyl, a (C1-C4) alkyl group or a (C1-C4) alkoxy group, or an amino group of the general formula NR3R4 (wherein, R3 and R4 each independently represent a hydrogen atom or a (C1-C4) alkyl group, or together with the nitrogen atom bearing them, form a pyrrolidine ring, a piperidine ring or a morpholine ring, or a phenyl group optionally substituted with the atoms or groups defined for the above symbol X)] a compound having the formula of or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is [Chemical formula] a compound having the formula of or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0033] In certain embodiments, the GlyT1 inhibitor is of formula VII [Chemical formula] [wherein, R 1 is -(CH2) n -R 1a (wherein, n is independently 0 to 6, and R 1a is (1) unsubstituted or C substituted with 1 to 6 halogens or hydroxy 1~6 alkyl, (2) phenyl substituted with R 2a , R 2b and R 2c , (3) unsubstituted or C 1~6 alkyl, 1 to 6 halogens, hydroxy or -NR 10 R 11 substituted C 3~6 cycloallyl, (4) unsubstituted or 1 to 6 halogens, hydroxy or -NR 10 R 11 substituted -O-C 1~6 alkyl, (5) -CO2R 9 (wherein, R9 is (a) hydrogen, (b) -C 1~6 alkyl which is unsubstituted or substituted with 1 to 6 fluoros, (c) benzyl, and (d) independently selected from phenyl), (6) -NR 10 R 11 (wherein, R 10 and R 11 are (a) hydrogen, (b) -C alkyl substituted with hydroxy, 1 to 6 fluoros or -NR 12 R 13 (wherein, R 12 and R 13 are independently selected from hydrogen and -C 1~6 alkyl), (c) -C 1~6 alkyl substituted with hydroxy, 1 to 6 fluoros or -NR 12 R 13 or unsubstituted -C 3~6 cycloalkyl, (d) benzyl, (e) independently selected from phenyl), and (7) -CONR 10 R 11 selected from the group consisting of); R2 is (1) R 2a , R 2b and R 2cphenyl which is substituted by, (2) unsubstituted or 1 to 6 halogens, hydroxy, -NR 10 R 11 , C alkyl which is substituted by phenyl or a heterocyclic ring 1~8 (wherein the phenyl or heterocyclic ring is substituted by R 2a , R 2b and R 2c ), (3) unsubstituted or 1 to 6 halogens, hydroxy or -NR 10 R 11 substituted cycloalkyl, and (4) unsubstituted or 1 to 6 halogens, hydroxy or -NR 3~6 substituted -C 10 alkyl-(C 11 cycloalkyl) selected from the group consisting of; R 1~6 alkyl-(C 3~6 cycloalkyl) selected from the group consisting of; R 2a , R 2b and R 2c are independently selected from the group consisting of (1) hydrogen, (2) halogen, (3) unsubstituted or (a) 1 to 6 halogens, (b) phenyl, (c) C 3~6 cycloalkyl, or (d) -NR 10 R 11 substituted -C 1~6 alkyl, (4) unsubstituted or 1 to 6 halogen substituted -O-C 1~6 alkyl, (5) hydroxy, (6) -SCF3, (7) -SCHF2, (8) -SCH3, (9) -CO2R 9 , (10) -CN, (11) -SO2R 9 , (12) -SO2-NR 10 R 11 , (13) -NR 10 R 11 , (14) -CONR 10 R 11 , and (15) -NO2; R 3 is (1) unsubstituted or 1 to 6 halogens, hydroxyl or -NR 10 R 11 substituted C 1~6alkyl, (2) unsubstituted or substituted with 1 to 6 halogens, hydroxyls or -NR 10 R 11 and is selected from the group consisting of C 3~6 cycloalkyl, where R 4 and R 5 are independently selected from the group consisting of (1) hydrogen and (2) C 1~6 alkyl which is unsubstituted or substituted with halogen or hydroxyl, or R 4 and R 5 together form a C 3~6 cycloalkyl ring; A is selected from the group consisting of (1) -O- and (2) -NR 10 -; m is zero or 1, where when m is zero, R 2 is directly bonded to the carbonyl] compounds and pharmaceutically acceptable salts thereof, as well as individual enantiomers and diastereomers thereof or pharmaceutically acceptable salts thereof, or prodrugs of the compounds or pharmaceutically acceptable salts thereof. In certain such embodiments, the GlyT1 inhibitor is

Chemical formula

[0034] or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the GlyT1 inhibitor is of formula VIII

Chemical formula

Chemical formula

Chemical formula

[0035] In certain embodiments, the GlyT1 inhibitor is the following:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0036] In certain embodiments, the GlyT1 inhibitor is of formula IX [Chemical Formula] [wherein, R 1 represents phenyl, or a 5- or 6-membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from O, N or S, wherein the phenyl or heteroaryl is optionally substituted with one or more R 3 ; R 2 represents aryl, a 5- or 6-membered monocyclic heteroaryl, or an 8- to 10-membered bicyclic heteroaryl, the monocyclic or bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from O, N or S, wherein the aryl or heteroaryl is optionally substituted with one or more R 4 ; R 3 is halogen, C 1~4 -alkyl or C 3~6 -cycloalkyl, wherein the C 1~4 -alkyl or C 3~6 -cycloalkyl is optionally substituted with one or more halogens; R 4 is halogen, -CN, C 1~4 -alkyl, C 3~6 -cycloalkyl, -C 1~3 -alkyl-C 3~6 -cycloalkyl or -O-C 1~6 alkyl, wherein the C 1~4 -alkyl, C 3~6 -cycloalkyl, -C 1~3 -alkyl-C 3~6 -cycloalkyl or -O-C 1~6 -alkyl is optionally substituted with one or more halogens] The compound, or a pharmaceutically acceptable salt thereof, or a tautomer or stereoisomer of the compound or a pharmaceutically acceptable salt thereof, or a mixture of any of the foregoing.

[0037] In certain embodiments, the GlyT1 inhibitor is of formula X [Chemical formula] [wherein, R 1 is selected from the group consisting of: a) a 5- or 6-membered monocyclic heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of O, N and S(O)r; b) a 5- or 6-membered monocyclic partially saturated heterocycloalkyl having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, N and S(O); and c) a 9- or 10-membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, N and S(O) (wherein r is 0, 1 or 2); wherein each of said groups a), b) and c) is optionally substituted with one or more substituents independently selected from the group consisting of C r -alkyl-, C 1~4 -alkyl-O-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 1~4 -cycloalkyl- and C 3~6 -cycloalkyl-O-; and when the substituent is present, it is bonded to a nitrogen ring atom, and said substituent is selected from the group consisting of C 3~6 -alkyl-, C 1~4 -alkyl-CO-, C 1~4 -cycloalkyl- and C 3~6 -cycloalkyl-CO-; wherein said C 3~6 -alkyl-, C 1~4 -alkyl-O-, C 1~4 -alkyl-CO-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 1~4 -cycloalkyl-, C 3~6 -cycloalkyl-CO- or C 3~6 -cycloalkyl-CO- or C 3~6-Cycloalkyl-O- may each be substituted by one or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F and -CN; R 2 is hydrogen, C 1~4 -alkyl-, C 1~4 -alkyl-O-, -CN and C 3~6 -cycloalkyl-, where the C 1~4 -alkyl-, C 1~4 -alkyl-O- and C 3~6 -cycloalkyl- groups may each be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F and -CN; R 3 is C 1~6 -alkyl-O-, C 3~6 -cycloalkyl-O-, morpholino, pyrazolyl, and 4- to 7-membered monocyclic heterocycloalkyl-O- having 1 oxygen atom as a ring member and optionally 1 or 2 heteroatoms selected independently from the group consisting of O, N and S(O) s (where s = 0, 1 or 2), and is selected from the group consisting of, where the C 1~6 -alkyl-O- and the C 3~6 -cycloalkyl-O- may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -alkyl-, C 3~6 -cycloalkyl-, C 1~6 -alkyl-O- and C 3~6 -cycloalkyl-O-; R 4 is hydrogen; or R 3 and R 4 together with the ring atoms of the phenyl group to which they are attached form a 4-, 5- or 6-membered monocyclic partially saturated heterocycloalkyl, or each of which is O, N and S(O) sIt may form a heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of (where s = 0, 1 or 2), where R in general formula (I) 3 There must be one ring oxygen atom directly bonded to the ring carbon atom of the phenyl group to which it is bonded; where the heterocycloalkyl group is fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -alkyl-, C 3~6 -cycloalkyl-, C 1~6 -alkyl-O-, C 3~6 -cycloalkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O- and tetrahydropyranyl-O- and may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of; R 5 is hydrogen; R 6 is hydrogen, C 1~4 -alkyl-SO2-, C 3~6 -cycloalkyl-SO2 and -CN; R 7 is hydrogen; or a) R 6 and R 7 or b) R 6 and R 5 One of the pair forms a 5- or 6-membered partially saturated monocyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, N and S(O) u (where u = 0, 1 or 2), where there must be one -SO2- atom directly bonded to the ring carbon atom of the phenyl group to which R in general formula (I) is bonded, where the heterocycloalkyl group is fluoro, -CF3, -CHF2, -CH2F, -CN, C 6 is bonded, where the heterocycloalkyl group is fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -alkyl-, C 1~6 -alkyl-O- and C 3~6A compound optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of -cycloalkyl-O-, or a pharmaceutically acceptable salt thereof. In certain such embodiments, the GlyT1 inhibitor is of the formula

Chemical Structure

[0038] In some embodiments, the GlyT1 inhibitor is of formula XI

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0039] In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0040] In certain embodiments, the subject is a subject in need thereof.

[0041] In certain embodiments, a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount. BRIEF DESCRIPTION OF THE DRAWINGS

[0042]

Figure 1

[0043]

Figure 2

[0044]

Figure 3

[0045]

Figure 4

[0046]

Figure 5

[0047]

Figure 6

[0048] **Detailed Description of the Application** Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed embodiments belong.

[0049] As used herein, the terms "a" or "an" mean "at least one" or "one or more than one" unless the context clearly dictates otherwise.

[0050] As used herein, the term "about" means approximations and minor variations that would not significantly affect the implementation of the disclosed embodiments. When numerical limitations are used, unless otherwise indicated by the context, "about" means that the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments.

[0051] The term "acyl" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)-, preferably alkyl C(O)-.

[0052] As used herein, the term "acylamino" means an amino group substituted by an acyl group (e.g., -O-C(=O)-H or -O-C(=O)-alkyl). Examples of acylamino are -NHC(=O)H or -NHC(=O)CH3. The term "lower acylamino" refers to an amino group substituted by a lower acyl group (e.g., -O-C(=O)-H or -O-C(=O)-C 1~6 alkyl). Examples of lower acylamino are -NHC(=O)H or -NHC(=O)CH3.

[0053] The term "acyloxy" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)O-, preferably alkyl C(O)O-.

[0054] As used herein, the term "alkenyl" means a straight or branched alkyl group having one or more double carbon-carbon bonds and 2 to 20 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. In some embodiments, the alkenyl chain is 2 to 10 carbon atoms in length, 2 to 8 carbon atoms in length, 2 to 6 carbon atoms in length, or 2 to 4 carbon atoms in length.

[0055] The terms "alkoxy", "phenyloxy", "benzyloxy", and "pyrimidinyl-oxy" refer to an alkyl group, a phenyl group, a benzyl group, or a pyrimidinyl group, respectively, each optionally substituted and attached through an oxygen atom. For example, the term "alkoxy" means a straight-chain or branched -O-alkyl group having from 1 to 20 carbon atoms, and includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, and the like. In some embodiments, the alkoxy chain has a length of from 1 to 10 carbon atoms, from 1 to 8 carbon atoms, from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 2 to 10 carbon atoms, from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms.

[0056] As used herein, the term "alkyl" means a straight-chain or branched saturated hydrocarbon group. The alkyl group can contain from 1 to 20, 2 to 20, 1 to 10, 2 to 10, 1 to 8, 2 to 8, 1 to 6, 2 to 6, 1 to 4, 2 to 4, 1 to 3, or 2 or 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, t-butyl, isobutyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl, 2,2-dimethyl-1-propyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, and the like.

[0057] As used herein, the term "alkylamino" means an amino group substituted by an alkyl group having 1 to 6 carbon atoms. An example of alkylamino is -NHCH2CH3.

[0058] As used herein, the term "alkylene" or "alkylenyl" means a divalent alkyl linking group. Examples of alkylene (or alkylenyl) are methylene or methylenyl (-CH2-).

[0059] As used herein, the term "alkylthio" means an -S-alkyl group having 1 to 6 carbon atoms. An example of an alkylthio group is -SCH2CH3.

[0060] As used herein, the term "alkynyl" means a straight-chain or branched alkyl group having one or more triple carbon-carbon bonds and 2 to 20 carbon atoms, including, but not limited to, acetylene, 1-propylene, 2-propylene, etc. In some embodiments, the alkynyl chain is 2 to 10 carbon atoms in length, 2 to 8 carbon atoms in length, 2 to 6 carbon atoms in length, or 2 to 4 carbon atoms in length.

[0061] The term "amide", as used herein, refers to the group [Chemical formula] (wherein each R 30 independently represents hydrogen or a hydrocarbyl group, or two Rs 30 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure).

[0062] As used herein, the term "amidinio" means -C(=NH)NH2.

[0063] The terms "amine" and "amino" are recognized in the art and refer to both unsubstituted and substituted amines, as well as their salts, for example, [Chemical formula] (wherein each R 30 independently represents hydrogen or a hydrocarbyl group, or two Rs 30 together with the N atom to which they are attached complete a heterocyclic ring having 4 to 8 atoms in the ring structure) refers to a moiety that can be represented by

[0064] As used herein, the term "aminoalkoxy" means an alkoxy group substituted by an amino group. An example of aminoalkoxy is -OCH2CH2NH2.

[0065] As used herein, the term "aminoalkyl" means an alkyl group substituted by an amino group. An example of aminoalkyl is -CH2CH2NH2.

[0066] As used herein, the term "aminosulfonyl" means -S(=O)2NH2.

[0067] As used herein, the term "aminoalkylthio" means an alkylthio group substituted by an amino group. An example of aminoalkylthio is -SCH2CH2NH2.

[0068] As used herein, the term "amphiphilic" means a three-dimensional structure having distinct hydrophobic and hydrophilic regions. Amphiphilic compounds preferably have the presence of both hydrophobic and hydrophilic elements.

[0069] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrates, such as wild animals, domesticated animals, and livestock.

[0070] As used herein, the term "aryl" means a monocyclic, bicyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon. In some embodiments, the aryl group has 6 to 20 carbon atoms, or 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, and the like. Examples of aryl groups include, but are not limited to, [Chemical formula] [Chemical formula] include.

[0071] As used herein, the term "arylalkyl" means a C 1~6 alkyl substituted by aryl.

[0072] As used herein, the term "arylamino" means an amino group substituted by an aryl group. An example of arylamino is -NH(phenyl).

[0073] As used herein, the term "arylene" means an aryl linking group, i.e., an aryl group that links one group to another group in a molecule.

[0074] The term "carbamate" is recognized in the art and the group [Chemical formula] (wherein R 29 and R 30 each independently represents hydrogen or a hydrocarbyl group, such as an alkyl group, or R 29 and R 30 together with the intervening atoms complete a heterocyclic ring having 4 to 8 atoms in the ring structure).

[0075] As used herein, the term "carbamoyl" means -C(=O)NH2.

[0076] As used herein, the term "carbocycle" means a 5- or 6-membered saturated or unsaturated cyclic ring optionally containing O, S, or N atoms as part of the ring. Examples of carbocycles include, but are not limited to, cyclopentyl, cyclohexyl, cyclopenta-1,3-diene, phenyl, and any of the heterocycles listed above.

[0077] The term "carbocyclic alkyl", as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0078] The term "carbonate" is recognized in the art and refers to the group -OCO2-R 30 (wherein R 30 represents a hydrocarbyl group).

[0079] The term "carboxy", as used herein, refers to the group represented by the formula -CO2H.

[0080] As used herein, the term "carrier" means a diluent, adjuvant, or excipient administered with a compound. A pharmaceutical carrier can be a liquid, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. A pharmaceutical carrier can also be physiological saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. In addition, auxiliary agents, stabilizers, thickening agents, lubricants, and coloring agents can be used.

[0081] As used herein, the term "compound" means all of the stereoisomers, tautomers, and isotopes of the compounds described herein.

[0082] As used herein, the terms "comprising" (and any form of comprising such as "comprise", "comprises" and "comprised"), "having" (and any form of having such as "have" and "has"), "including" (and any form of including such as "includes" and "include"), or "containing" (and any form of containing such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0083] As used herein, the term "contacting" means bringing two elements together in an in vitro or in vivo system. For example, "contacting" a GlyT1 transporter inhibitor with the GlyT1 transporter of an individual or patient or cell includes not only administration of the compound to the individual or patient, e.g., a human, but also introducing the compound into a sample containing, e.g., a cell preparation or a purified preparation containing the GlyT1 transporter.

[0084] As used herein, the term "cyano" means -CN.

[0085] As used herein, the term "cycloalkyl" means a non-aromatic cyclic hydrocarbon and includes cyclic alkyl, alkenyl, and alkynyl groups containing up to 20 ring-forming carbon atoms. The cycloalkyl group may include monocyclic or polycyclic ring systems, such as fused ring systems, bridged ring systems, and spiro ring systems. In some embodiments, the polycyclic ring system includes 2, 3, or 4 fused rings. The cycloalkyl group can contain 3 to 15, 3 to 10, 3 to 8, 3 to 6, 4 to 6, 3 to 5, or 5 or 6 ring-forming carbon atoms. The ring-forming carbon atoms of the cycloalkyl group can be optionally substituted by oxo or sulfide. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, etc. Also included in the definition of cycloalkyl are moieties having one or more aromatic rings fused to the cycloalkyl ring (having a bond common to the cycloalkyl ring), such as benzo or thienyl derivatives of pentane, pentene, hexane, etc. (e.g., 2,3-dihydro-1H-inden-1-yl or 1H-inden-2(3H)-one-1-yl).

[0086] As used herein, the term "cycloalkylalkyl" means a C 1~6 alkyl substituted by cycloalkyl.

[0087] As used herein, the term "dialkylamino" means an amino group substituted by two alkyl groups each having 1 to 6 carbon atoms.

[0088] As used herein, the term "diazamino" means -N(NH2)2.

[0089] The term "ester", as used herein, means the group -C(O)OR 30(wherein R 30 represents a hydrocarbyl group).

[0090] The term "ether", as used herein, refers to a hydrocarbyl group linked through oxygen to another hydrocarbyl group. Thus, an ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. The ether can be either symmetric or asymmetric. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. The ether includes an "alkoxyalkyl" group, which can be represented by the general formula alkyl-O-alkyl.

[0091] As used herein, the terms "apparently amphiphilic" or "surface amphiphilic" mean a compound having polar and nonpolar side chains that adopt a conformation that results in the separation of polar (hydrophilic) and nonpolar (hydrophobic) side chains on opposite faces or separate regions of the structure or molecule.

[0092] As used herein, the term "glycine transporter" or "GlyT" refers to a membrane protein that facilitates the transport of glycine across the cell membrane of a cell. Non-limiting examples of glycine transporters include glycine transporter 1 (GlyT1) and glycine transporter 2 (GlyT2).

[0093] As used herein, the terms “GlyT1” or “GlyT1 transporter” mean the sodium and chloride-dependent glycine transporter 1, also known as glycine transporter 1, which in humans is the protein encoded by the SLC6A9 gene (Kim KM, Kingsmore SF, Han H, Yang-Feng TL, Godinot N, Seldin MF, Caron MG, Giros B (Jun 1994). "Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes". Mol Pharmacol. 45 (4): 608-17; Jones EM, Fernald A, Bell GI, Le Beau MM (Nov 1995). "Assignment of SLC6A9 to human chromosome band 1p33 by in situ hybridization". Cytogenet Cell Genet. 71 (3): 211), which are hereby incorporated by reference in their entirety.

[0094] As used herein, the terms "GlyT2" or "GlyT2 transporter" mean the sodium- and chloride-dependent glycine transporter 2, also known as glycine transporter 2, which in humans is the protein encoded by the SLC6A5 gene (Morrow JA, Collie IT, Dunbar DR, Walker GB, Shahid M, Hill DR (November 1998). "Molecular cloning and functional expression of the human glycine transporter GlyT2 and chromosomal localisation of the gene in the human genome". FEBS Lett. 439 (3): 334-40), which is hereby incorporated by reference in its entirety.

[0095] As used herein, the term "GlyT1 inhibitor" means a compound that inhibits or blocks the activity of the GlyT1 transporter and includes compounds that inhibit the activity of any isoform of GlyT1. Non-limiting examples of GlyT1 inhibitors are provided herein. In some embodiments, the GlyT1 inhibitor is a specific GlyT1 inhibitor, which means that the inhibitor has a higher inhibitor activity against GlyT1 compared to GlyT2. In some embodiments, the inhibitor has at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% selectivity, or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% selectivity for inhibiting GlyT1 compared to GlyT2. In some embodiments, the GlyT1 inhibitor inhibits GlyT1 but does not inhibit or significantly inhibit the activity of GlyT2. A GlyT1 inhibitor that does not significantly inhibit the activity of GlyT2, in that case, inhibits the activity of GlyT2 by less than 5%, 4%, 3%, 2% or 1%. The selectivity of the GlyT1 inhibitor is determined based on assays known in the art, for example, assays described in published academic papers (B. N. Atkinson, S. C. Bell, M. De Vivo, L. R. Kowalski, S. M. Lechner, V. I. Ognyanov, C.-S. Tham, C. Tsai, J. Jia, D. Ashton and M. A. Klitenick, ALX 5407: A Potent, Selective Inhibitor of the hGlyT1 Glycine Transporter, Molecular Pharmacology December 2001, 60 (6) 1414-1420), which is hereby incorporated by reference in its entirety.

[0096] As used herein, the term "GlyT2 inhibitor" means a compound that inhibits or blocks the activity of the GlyT2 transporter, and includes compounds that inhibit the activity of any isoform of GlyT2. In some embodiments, the GlyT2 inhibitor is a non-specific inhibitor, which means that it can also inhibit or block the activity of GlyT1. In some embodiments, the GlyT2 inhibitor is a specific GlyT2 inhibitor, which means that the inhibitor has a higher inhibitor activity against GlyT2 compared to GlyT1. In some embodiments, the inhibitor has a selectivity of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% compared to GlyT1, or inhibits GlyT2 with a selectivity of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%. In some embodiments, the GlyT2 inhibitor inhibits GlyT2 activity but does not inhibit or significantly inhibit the activity of GlyT1. A GlyT2 inhibitor that does not significantly inhibit the activity of GlyT1 inhibits the activity of GlyT1 by less than 5%, 4%, 3%, 2% or 1% in that case. The selectivity of the GlyT2 inhibitor is determined based on assays known in the art, for example, assays based on those described in published academic papers (B. N. Atkinson, S. C. Bell, M. De Vivo, L. R. Kowalski, S. M. Lechner, V. I. Ognyanov, C.-S. Tham, C. Tsai, J. Jia, D. Ashton and M. A. Klitenick, ALX 5407: A Potent, Selective Inhibitor of the hGlyT1 Glycine Transporter, Molecular Pharmacology December 2001, 60 (6) 1414-1420), which is hereby incorporated by reference in its entirety.

[0097] As used herein, the term "guanidino" means -NH(=NH)NH2.

[0098] As used herein, the term "halo" means a halogen group and includes, but is not limited to, fluoro, chloro, bromo and iodo.

[0099] As used herein, the term "haloalkoxy" means an -O-haloalkyl group. An example of a haloalkoxy group is OCF3.

[0100] As used herein, the term "haloalkyl" means a C 1~6 alkyl group having one or more halogen substituents. Examples of haloalkyl groups include, but are not limited to, CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, CH2CF3, and the like.

[0101] As used herein, the term "heteroaryl" means an aromatic heterocyclic ring having up to 20 ring-forming atoms (e.g., C) and having at least one heteroatom (ring-forming atom) such as sulfur, oxygen or nitrogen as a ring member. In some embodiments, the heteroaryl group has at least one or more heteroatom ring-forming atoms, each of which is independently sulfur, oxygen or nitrogen. In some embodiments, the heteroaryl group has 3 to 20 ring-forming atoms, 3 to 10 ring-forming atoms, 3 to 6 ring-forming atoms, or 3 to 5 ring-forming atoms. In some embodiments, the heteroaryl group contains 2 to 14 carbon atoms, 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, the heteroaryl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl (such as indol-3-yl), pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyranyl, oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, pyrazolyl, indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanyl, phenoxazinyl groups and the like.Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine and 2-aminopyridine.

[0102] As used herein, the term "heteroarylalkyl" means a C 1~6 alkyl group substituted by a heteroaryl group.

[0103] As used herein, the term "heteroarylamino" means an amino group substituted by a heteroaryl group. An example of heteroarylamino is -NH-(2-pyridyl).

[0104] As used herein, the term "heteroarylene" means a heteroaryl linking group, i.e., a heteroaryl group that links one group to another group in a molecule.

[0105] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen, oxygen and sulfur.

[0106] As used herein, the term "heterocyclic ring" or "heterocyclic ring system" means a monocyclic or bicyclic 5- to 7-membered, or a bicyclic 7- to 10-membered heterocyclic ring system, wherein any ring thereof may be saturated or unsaturated, which is composed of carbon atoms and 1 to 3 heteroatoms selected from N, O and S, wherein the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized, and includes any bicyclic group in which any of the heterocyclic rings defined above is fused to a benzene ring. Rings containing one oxygen or sulfur, 1 to 3 nitrogen atoms, or one oxygen or sulfur in combination with 1 or 2 nitrogen atoms are particularly useful. The heterocyclic ring may be bonded by any heteroatom or carbon atom, which results in the creation of a stable structure. Examples of heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and oxadiazolyl. Morpholino is the same as morpholinyl.

[0107] As used herein, the term "heterocycloalkyl" means a non-aromatic heterocyclic ring having up to 20 ring-forming atoms, including cyclic alkyl, alkenyl, and alkynyl groups, where one or more ring-forming carbon atoms are replaced by heteroatoms such as O, N, or S atoms. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., fused, bridged, or spiro). In some embodiments, the heterocycloalkyl group has 1 to 20 carbon atoms, or 3 to 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 or 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like. Additionally, the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by oxo or sulfide. For example, a ring-forming S atom can be substituted by 1 or 2 oxo (forming S(O) or S(O)2). For another example, a ring-forming C atom can be substituted by oxo (forming a carbonyl).Also, a moiety having one or more aromatic rings fused to a non-aromatic heterocyclic ring (having a bond common to the non-aromatic heterocyclic ring) is included in the definition of heterocycloalkyl, and includes, but is not limited to, heterocyclic pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl and benzo derivatives such as indolene, isoindolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindolin-1-one-3-yl and 3,4-dihydroisoquinolin-1(2H)-one-3-yl groups. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally substituted by oxo or sulfide.

[0108] As used herein, the term "heterocycloalkylalkyl" refers to a C 1~6 alkyl substituted by heterocycloalkyl.

[0109] As used herein, the term "hydroxy" or "hydroxyl" means an -OH group.

[0110] As used herein, the term "hydroxyalkyl" or "hydroxylalkyl" means an alkyl group substituted by a hydroxyl group. Examples of hydroxyalkyl include, but are not limited to, -CH2OH and -CH2CH2OH.

[0111] As used herein, the terms "individual" or "patient", used interchangeably, mean any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates such as humans.

[0112] As used herein, the phrase "inhibitory activity", e.g., enzyme or transporter activity, means reducing the activity of an enzyme or transporter, e.g., the GlyT1 transporter, by any measurable amount.

[0113] As used herein, the phrase "in need thereof" means that an animal or mammal is identified as having a need for a particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, an animal or mammal may be in need thereof. In some embodiments, the animal or mammal is in or is progressing into an environment where a particular disease, disorder or condition is prevalent.

[0114] As used herein, the phrase "gelatinizable in situ" means not only a low-viscosity liquid that forms a gel upon contact with the eye or tear fluid outside the eye, but also more viscous liquids such as semi-fluid and thixotropic gels that exhibit a substantial increase in viscosity or gel firmness upon administration to the eye.

[0115] As used herein, the phrase "an integer from X to Y" means any integer including the endpoints. For example, the phrase "an integer from X to Y" means 1, 2, 3, 4 or 5.

[0116] The term "lower", when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, means a group having 10 or fewer non-hydrogen atoms, preferably 6 or fewer non-hydrogen atoms, in the substituent. "Lower alkyl" refers to an alkyl group containing, for example, 10 or fewer carbon atoms, preferably 6 or fewer carbon atoms. In certain embodiments, whether they appear alone or in combination with other substituents, such as in a description where hydroxyalkyl and aralkyl (in this case, for example, when counting carbon atoms in the alkyl substituent, atoms within the aryl group are not counted), the acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituents as defined herein are each lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy, respectively.

[0117] As used herein, the term "mammal" means a rodent (i.e., mouse, rat or guinea pig), monkey, cat, dog, cow, horse, pig or human. In some embodiments, the mammal is a human.

[0118] As used herein, the term "N-alkyl" refers to an alkyl chain substituted with an amine group. Non-limiting examples include, but are not limited to,

Chemical formula

[0119] As used herein, the term "nitro" means -NO2.

[0120] As used herein, the term "n-membered" (where n is an integer) typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl ring.

[0121] As used herein, the phrase "ophthalmically acceptable" means having no persistent adverse effects on the treated eye or its function, or on the overall health of the subject being treated. However, transient effects such as mild irritation or a "stinging" sensation are common with topical instillation of a drug, and the presence of such transient effects will be recognized as not inconsistent with a composition, formulation or ingredient (e.g., excipient) being "ophthalmically acceptable" as defined herein.

[0122] As used herein, the phrase "optionally substituted" means that a substituent is optional, and thus includes both unsubstituted and substituted atoms and moieties. A "substituted" atom or moiety indicates that any hydrogen on the specified atom or moiety can be replaced with a selection from the indicated substituents, provided that the normal valence of the specified atom or moiety is not exceeded and that the substitution results in a stable compound. For example, if a methyl group is optionally substituted, the three hydrogen atoms on the carbon atom can be replaced with substituents.

[0123] As used herein, the phrase "pharmaceutically acceptable" means a compound, material, composition and / or dosage form that is suitable for use in contact with human and animal tissues within the scope of sound medical judgment. In some embodiments, "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, more specifically in humans.

[0124] "Pharmaceutically acceptable salts" are intended to mean salts of the free acids or free bases of the compounds represented herein that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject from other perspectives. Generally, see S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are free of undue toxicity, irritation, or allergic response, are pharmacologically effective, and are suitable for contact with the tissues of a subject. The compounds described herein can have sufficient acidic groups, sufficient basic groups, both types of functional groups, or more than one of each type, and can thus react with several inorganic or organic bases as well as inorganic and organic acids to form pharmaceutically acceptable salts.

[0125] For compounds described herein that contain basic groups such as amines, pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphorous acid, etc., or organic acids such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidic acids such as glucuronic acid or galacturonic acid, alpha-hydroxy acids such as mandelic acid, citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, sulfonic acids such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid, or any compatible mixture of acids such as those shown as examples herein, and by treatment of the free base with any other acids and mixtures thereof considered to be equivalents or acceptable substitutions in view of the normal level of skill in the art.

[0126] For the compounds described herein containing acidic groups such as carboxylic acid groups, base addition salts can be prepared by treating such compounds with a sufficient amount of the desired base in any suitable manner available in the art, for example, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, salts of lithium, sodium, potassium, calcium, ammonium, zinc or magnesium, or other metal salts; organic amino salts, such as alkyl, dialkyl, trialkyl or tetraalkylammonium salts.

[0127] Other examples of pharmaceutically acceptable salts include, but are not limited to, camphorsulfonate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate and mandelate. An enumeration of other suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0128] The neutral form of the compound is preferably regenerated by contacting the salt with a base or an acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise, the salts are equivalent to the parent form of the compound for the purposes of this application.

[0129] As used herein, the term "phenyl" means -C6H5. The phenyl group may be unsubstituted or substituted with one, two or three suitable substituents.

[0130] The terms "polycyclic", "polycycle" and "polycyclic ring" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings". Each of the polycyclic rings may be substituted or unsubstituted. In certain embodiments, each of the polycyclic rings contains from 3 to 10 atoms, preferably from 5 to 7 atoms, in the ring.

[0131] As used herein, the term "prodrug" means a derivative of a known direct-acting drug, which derivative has enhanced delivery properties and therapeutic value compared to the drug and is converted to the active drug by an enzymatic or chemical process. A common method for making a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to yield the desired molecule. In certain embodiments, the prodrug is converted by the enzymatic activity of the host animal. For example, a prodrug having a nitro group on an aromatic ring can be reduced by reductase in vivo to yield the desired amino group of the corresponding active compound. In another example, a functional group such as a hydroxyl, carbonate, or carboxylic acid in the parent compound is present as an ester, which can be cleaved by an esterase. In addition, an amine group in the parent compound is present in a carbamate, N-alkylated, or N-acylated form, among others (Simplicio et al, "Prodrugs for Amines," Molecules, (2008), 13:519-547). In certain embodiments, some or all of the compounds described herein in the formulations represented above can be replaced with the corresponding suitable prodrugs.

[0132] As used herein, the term "purified," when referring to an isolate, means that the isolate contains, by weight of the isolate, at least 90%, at least 95%, at least 98%, or at least 99% of the compound described herein.

[0133] As used herein, the phrase "quaternary ammonium salt" is a derivative of the disclosed compounds having one or more tertiary amine moieties, where at least one tertiary amine moiety in the parent compound is alkylated (and the cation is Cl - , CH3COO - and CF3COO -(counterbalanced by anions such as), for example, modified by converting a tertiary amine moiety to a quaternary ammonium cation via methylation or ethylatation.

[0134] As used herein, the term "semicarbazone" means =NNHC(=O)NH2.

[0135] As used herein, the phrase "solubilizing agent" means an agent that results in the formation of a micellar solution or true solution of a drug.

[0136] As used herein, the term "solution / suspension" means a liquid composition in which a first portion of the active agent is present in solution and a second portion of the active agent is present in a suspension in a liquid matrix in a particular form.

[0137] As used herein, the phrase "substantially isolated" means a compound that is at least partially or substantially separated from the environment in which it is formed or detected.

[0138] The term "substituted" refers to a moiety having a substituent that replaces hydrogen on one or more carbons of a backbone. It is understood that "substituted" or "substituted with" is implicit, provided that such substitution follows the accepted valences of the atoms and substituents being substituted and that the substitution results in a stable compound that does not undergo spontaneous conversion, for example, by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all acceptable substituents of an organic compound. In a broad aspect, acceptable substituents include substituents of acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. Acceptable substituents can be one or more and can be the same or different for a suitable organic compound. For the purposes of this application, a heteroatom such as nitrogen can have a hydrogen substituent and / or any acceptable substituent of the organic compounds described herein that satisfies the valence of the heteroatom.

[0139] Suitable substituents can include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. One of ordinary skill in the art will understand that a substituent can itself be substituted, where appropriate. References to chemical moieties herein are understood to include substituted variants, unless specifically stated as "unsubstituted". For example, a reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0140] The term "sulfate" is recognized in the art and refers to the group -OSO3H or a pharmaceutically acceptable salt thereof.

[0141] The term "sulfonamide" is recognized in the art and has the general formula [Chemical formula] (wherein R 29 and R 30 each independently represents hydrogen or hydrocarbyl, such as alkyl, or R 29 and R 30 together with the intervening atoms complete a heterocyclic ring having 4 to 8 atoms in the ring structure) refers to a group represented by.

[0142] The term "sulfoxide" is recognized in the art and refers to the group -S(O)-R 30 (wherein R 30 represents hydrocarbyl).

[0143] The term "sulfonate" is recognized in the art and refers to the group SO3H or a pharmaceutically acceptable salt thereof.

[0144] The term "sulfone" is recognized in the art and refers to the group -S(O)2-R 30 (wherein R 30 represents hydrocarbyl).

[0145] As used herein, the phrase "therapeutically effective amount" means the amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response required by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human. The therapeutic effect depends on the disorder being treated or the desired biological effect. Thus, the therapeutic effect can be a reduction in the severity of the symptoms associated with the disorder and / or inhibition (partial or complete) of the progression of the disorder, or it can improve the treatment, cure, prevention, or elimination of the disorder or side effects. The amount required to elicit a therapeutic response can be determined based on the age, health, size, and gender of the subject. The optimal amount can also be determined based on monitoring the response of the subject to the treatment.

[0146] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0147] As used herein, the term "thioester" refers to the group -C(O)SR 30 or -SC(O)R 30 (wherein R 30 represents a hydrocarbyl).

[0148] As used herein, the term "thioether" is the equivalent for an ether in which oxygen is replaced by sulfur.

[0149] As used herein, the terms "treat", "treated" or "treating" mean both therapeutic treatment and prophylactic measures, where the purpose is to delay (reduce) an undesired physiological condition, disorder or disease, or to obtain a beneficial clinical outcome or a desired clinical outcome. Beneficial clinical outcomes or desired clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the degree of a condition, disorder or disease; stabilization of the condition, disorder or disease (i.e., does not worsen); delay or deceleration in the onset of progression of a condition, disorder or disease; recovery or remission of the condition, disorder or disease, whether detectable or undetectable (whether partial or total); recovery of at least one measurable physical parameter not necessarily recognized by the patient; or enhancement or improvement of a condition, disorder or disease. Treatment includes inducing a clinically significant response without an excessive level of side effects. Treatment also includes extending survival as compared to survival expected in the absence of treatment. Thus, "treatment of hepatic porphyria" means an activity that reduces or restores either the primary phenomenon or secondary symptoms associated with hepatic porphyria or other conditions described herein.

[0150] The term "urea" is recognized in the art and has the general formula [Chemistry] (wherein R 29 and R 30 each independently represents hydrogen or hydrocarbyl, such as alkyl, or the occurrence of R 29 together with R 30 and the intervening atoms completes a heterocyclic ring having 4 to 8 atoms in the ring structure).

[0151] At various places in this specification, the substituents of a compound may be disclosed in groups or ranges. It is specifically intended that the embodiments include each and all individual subcombinations of the members of such groups and ranges. For example, the term "C 1~6 alkyl" is specifically intended to individually disclose methyl, ethyl, propyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0152] For compounds in which a variable appears more than once, each variable may be a different moiety selected from the Markush groups that define the variable. For example, if a structure is described as having two R groups present simultaneously in the same compound, the two R groups can represent different moieties selected from the Markush groups defined for R. In another example, if a plurality of substituents are specified, for example, [Chemistry] in the form of, it is understood that the substituent R can occur s times on the ring and that R can be a different moiety at each occurrence. In the above example, if the variable T 1 is defined to include hydrogen, for example, if T 1 is CH2, NH, etc., any H can be replaced by a substituent.

[0153] It is further recognized that certain features described herein in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, various features described in the context of a single embodiment for the sake of brevity can also be provided separately or in any suitable sub-combination.

[0154] It is understood that this embodiment, where applicable, encompasses the use of stereoisomers, diastereomers, and optical stereoisomers of the compound, and mixtures thereof. Additionally, it is understood that stereoisomers, diastereomers, and optical stereoisomers of the compound, and mixtures thereof, are within the scope of the embodiment. As a non-limiting example, the mixture may be a racemate or the mixture may contain one particular stereoisomer in a non-equivalent proportion relative to the others. Additionally, the compound can be provided as a substantially pure stereoisomer, diastereomer, and optical stereoisomer (such as an epimer).

[0155] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the embodiment unless otherwise indicated. Compounds containing an asymmetrically substituted carbon atom can be isolated in an optically active form or a racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolution of a racemic mixture or by stereoselective synthesis. Many geometric isomers, such as olefins, C=N double bonds, etc., can also be present in the compounds described herein, and all such stable isomers are provided herein. The cis and trans geometric isomers of the compound are also included within this embodiment and can be isolated as a mixture of isomers or as separate isomeric forms. When a compound capable of stereoisomerism or geometric isomerism is specified by its structure or name without specific reference to an R / S or cis / trans configuration, it is intended that all such isomers are contemplated.

[0156] In some embodiments, the composition comprises a compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is at least 90%, at least 95%, at least 98%, or at least 99%, or 100% enantiomerically pure, which means that the ratio of one enantiomer to the other in the composition is at least 90:1, at least 95:1, at least 98:1, or at least 99:1, or is completely in the form of one enantiomer over the other. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means that the substance in question constitutes less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% compared to the amount of the other enantiomer, for example, in the composition or mixture of compounds. For example, if a composition or mixture of compounds contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mole percent of the first enantiomer and only 2% of the second enantiomer.

[0157] In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means that the substance in question constitutes less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% compared to the amount of the other enantiomer, for example, in the composition or mixture of compounds. For example, if a composition or mixture of compounds contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mole percent of the first enantiomer and only 2% of the second enantiomer.

[0158] The resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art, including, for example, chiral HPLC, fractional recrystallization using a chiral resolution acid, which is an optically active organic acid that forms an optically active salt. Suitable resolving agents for the fractional recrystallization method include, but are not limited to, optically active acids such as tartaric acid in its D and L forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other suitable resolving agents for the fractional crystallization method include, but are not limited to, α-methylbenzylamine in a stereoisomerically pure form (e.g., S and R forms, or a diastereomerically pure form), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. The resolution of the racemic mixture can also be carried out by elution in a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The composition of the suitable elution solvent can be determined by those skilled in the art.

[0159] The compound may also contain tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond, along with the movement of a proton. Tautomeric forms include prototropic tautomers, which are protonation states of isomers having the same empirical formula and total charge. Examples of prototropic tautomers include, but are not limited to, keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms where a proton can occupy two or more positions in a heterocyclic system, including, but not limited to, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or can be stereochemically fixed in one form by appropriate substitution.

[0160] Glycine transporter inhibitors, such as GlyT1 inhibitors, including their pharmaceutically acceptable salts (e.g., the GlyT1 inhibitors disclosed herein), can also exist as hydrates and solvates, as well as in anhydrous and unsolvated forms. A "hydrate" is a compound that exists as a composition with water molecules. The composition can contain stoichiometric amounts of water, such as a monohydrate or dihydrate, or can contain a disordered amount of water. A "solvate" is a similar composition except that the solvent is other than water, such as methanol, ethanol, dimethylformamide, diethyl ether, etc. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. Mixtures of such solvates or hydrates can also be prepared. The origin of such solvates or hydrates can be from the crystallization solvent, inherent in the preparation or crystallization solvent, or an adjunct of such a solvent.

[0161] The compounds of the present application can exist in various polymorphic, pseudopolymorphic, or amorphous states, including their pharmaceutically acceptable salts and prodrugs. As used herein, the term "polymorph" refers to different crystalline forms of the same compound, as well as other solid-state molecular forms, such as hydrates, solvates, or salts of the same compound, i.e., pseudopolymorphs. Different crystalline polymorphs have different crystal structures due to different packings of molecules in the lattice as a result of changes in temperature, pressure, or variables in the crystallization process. Polymorphs differ from each other in their physical properties, such as X-ray diffraction characteristics, stability, melting point, solubility, or rate of dissociation in a particular solvent. Therefore, the form of crystalline polymorphs is an important aspect in the development of suitable dosage forms in the pharmaceutical industry.

[0162] Compounds can also contain atoms of all isotopes that occur in the intermediate or final compound. Isotopes include atoms that have the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0163] In some embodiments, the compound or a salt thereof is substantially isolated. Partial separation may include, for example, a composition enriched in the compound. Substantial separation may include a composition containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compound or a salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0164] While the disclosed compounds are preferred, other functional groups can be introduced into the compounds with the expectation of similar results. In particular, thioamides and thioesters are expected to have very similar properties. The distance between the aromatic rings can affect the geometric pattern of the compound and can be substituted as needed or this distance can be altered by introducing aliphatic chains of different lengths that can include amino acids, dicarboxylic acids or diamines. The distance between monomers within the compound and their relative orientation can also be altered by replacing the amide bond with a surrogate having additional atoms. Thus, replacement of a carbonyl group by a dicarbonyl changes the distance between monomers and the tendency of the dicarbonyl unit to select an anti-configuration of the two carbonyl moieties, altering the periodicity of the compound. Pyromellitic dianhydride represents yet another alternative to simple amide linkages, which can alter the conformation and physical properties of the compound. Recent methods of solid-phase organic chemistry (E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis A Practical Approach IRL Press Oxford 1989) enable here the synthesis of homodisperse compounds having a molecular weight approaching 5,000 daltons. Other substitution patterns are equally effective.

[0165] The compounds also include derivatives referred to as prodrugs.

[0166] Compounds containing an amine functional group can also form N-oxides. References herein to compounds containing an amine functional group include N-oxides as well. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Examples of N-oxides include N-oxides of the nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) (see Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience).

[0167] Accordingly, by reserving the right to append a proviso to, or exclude, any individual member of any such group that includes any subrange or combination of subranges within the group, this may be claimed in accordance with the range or in any similar manner, and less than the full measure of the present disclosure may be claimed for any reason. Further, by reserving the right to append a proviso to, or exclude, any individual substituent, analog, compound, ligand, structure or group thereof, or any member of such group, as recited in the claims, less than the full measure of the present disclosure may be claimed for any reason. Throughout the present disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications are hereby incorporated by reference into the present disclosure in their entirety to more fully describe the state of the art known to those of ordinary skill in the art as of the date of the present disclosure. In the event of any inconsistencies between the cited patents, patent applications and publications and the present disclosure, the present disclosure shall control.

[0168] For the sake of convenience, certain terms used in this specification, the examples and the claims are collected herein. Unless otherwise defined, all technical and scientific terms used in this disclosure shall have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0169] Embodiments of various compounds and their salts are provided. When a variable is not specifically listed, the variable can be any of the options described herein, except as otherwise recited or indicated by context.

[0170] In some embodiments, the compound is as described in the appended exemplary and non-limiting claims, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0171] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is of formula I

Chemical formula

[0172] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical Structure

[0173] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is Formula II

Chemical Structure

[0174] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0175] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [Chemical Formula] PF-3463275, a compound having the formula of or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is of Formula III [Chemical Formula] [wherein, Z 1 is selected from the group consisting of C 1~4 alkyl, C 3~6 cycloalkyl, C 1~4 alkoxy, C 1~4 alkylthio, haloC 1~4 alkyl, phenyl, haloC 1~4 alkoxy, halophenyl, C 1~4 alkylsulfinyl, C 1~4 alkylsulfonyl, bromo and chloro; Z 2 is selected from the group consisting of hydrogen, halogen, cyano, C 1~4 alkyl, phenyl, haloC 1~4 alkyl, haloC 1~4 alkoxy, halophenyl, C 1~4 alkoxyC 1~4 alkyl and C 3~6 cycloalkyl; Z 3 is selected from the group consisting of hydrogen, halogen, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 alkylthio, haloC 1~4 alkyl, haloC 1~4 alkoxy and C 3~6 cycloalkyl; Z 4 is selected from the group consisting of hydrogen, halogen, C1-3 alkyl, haloC 1~4 alkyl, C1~4 alkoxy, C 1~4 alkylthio, phenyl, halo C 1~4 alkoxy, halophenyl, C 1~4 alkoxy C 1~4 alkyl and C 3~6 is selected from the group consisting of cycloalkyl; Z 5 is hydrogen, fluoro, chloro, bromo, iodo, hydroxy, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 alkylthio, phenyl, halo C 1~4 alkyl, halo C 1~4 alkoxy, halophenyl, C 1~4 alkoxy C 1~4 alkyl and C 3~6 is selected from the group consisting of cycloalkyl; wherein Z 1 ~Z 5 if more than one of 1 Z 5 and Z 3 is methoxy, only Z 4 and Z 1~4 is methoxy, and R 3 and R4 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated A, 5, 6 or 7-membered carbocyclic ring optionally substituted with group Y’; Y is C 1~4 alkoxy, hydroxy, halo C 1~4 alkoxy and C 3~5 is selected from the group consisting of cycloalkyl; Y’ is C 1~4 alkyl, C 1~4 alkoxy, halogen, hydroxy, halo C 1~4 alkoxy, C 3~5 cycloalkyl and C 5~10 is selected from the group consisting of aryl, or Y’ forms a -CH2- or -CH2-CH2- bridge between two atoms on an A, 5, 6 or 7-membered carbocyclic ring; R5 and R 6 is, independently, C optionally substituted with one or more groups X 1~4 alkyl; or R 5 and R 6 together with the carbon atom to which they are attached form a saturated 5- or 6-membered carbon ring optionally substituted with one or more groups X', and R 5 and R6, when together with the carbon atom to which they are attached form a 5-membered saturated carbon ring, the ring may further contain an additional group of heteroatoms selected from O, N and S(O)m (where m = 0, 1 or 2); X is selected from the group consisting of halogen, hydroxy, C 1~4 alkoxy, haloC 1~4 alkyl, haloC 1~4 alkoxy and C 5~10 aryl; X' is selected from the group consisting of halogen, hydroxy, C 1~4 alkyl, C 1~4 alkoxy, haloC 1~4 alkyl, haloC 1~4 alkoxy and C 5~10 aryl; wherein R 3 , R 4 , R 5 and R 6 are not all simultaneously unsubstituted methyl; provided that, simultaneously, when Z 1 is propyloxy, Z 3 is chloro, Z 2 =Z 4 =Z 5 =H, and R 5 and R 6 are both methyl, R 3 and R 4 do not together with the nitrogen atom to which they are attached form a 2-methylpyrrolidine group; simultaneously, when Z 1 is methyl, Z 3 is methoxy, Z 2 =Z4=Z5=H, and R 5and R 6 When both are methyl, R 3 and R 4 together with the nitrogen atom to which they are attached do not form a pyrrolidine group] is a compound of or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [Chemical formula] is a compound having the formula of or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is of formula IV [Chemical formula] [wherein, Z is (CH2) n , O, S, SO, SO2 or N-R5; n is 0, 1 or 2; X is hydrogen, halogen, (C 1~6 ) alkyloxy, (C 3~6 ) cycloalkyloxy, (C 6~12 ) aryloxy, (C 6~12 ) aryl, thienyl, SR6, SOR6, SO2R6, NR6R6, NHR6, NH2, NHCOR6, NSO2R6, CN, COOR6, and 1 to 3 substituents independently selected from halogen, (C 6~12 ) aryl, (C 1~6 ) alkyloxy or (C 6~12 ) aryloxy optionally substituted (C 1~4 ) alkyl; or two substituents at adjacent positions together form a fused (C 5~6 ) aryl group, a fused (C 5~6 ) cycloalkyl ring or O-(CH2)m represents -O; m is 1 or 2; Y represents 1 to 3 substituents independently selected from hydrogen, halogen, (C 1~4 )alkyloxy, SR6, NR6R6, and (C 1~4 )alkyl optionally substituted with halogen; R1 is COOR7 or CONR8R9; R2 and R6 are (C 1~4 )alkyl; R3, R4 and R5 are independently hydrogen or (C 1~4 )alkyl; R7, R8 and R9 are independently hydrogen, (C 1~4 )alkyl, (C 6~12 )aryl or arylalkyl] is a compound of formula or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0180] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is of formula V

Chemical formula

[0181] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [Chemical Formula] is a compound having the formula of or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0182] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is of formula VI [Chemical Formula] [wherein, A represents a group of the general formula N-R1, a group of the general formula N+(O-)R1 or a group of the general formula N+(R’)R1 (wherein, R1 represents a hydrogen atom, or a linear or branched (C1-C7) alkyl group optionally substituted with one or more fluorine atoms, or a (C4-C7) cycloalkyl group, or a (C3-C7) cycloalkyl(C1-C3)alkyl group, or a phenyl(C1-C3)alkyl group optionally substituted with one or two hydroxyl groups or methoxy groups, or a (C2-C4) alkenyl group, or a (C2-C4) alkynyl group); R’ represents a linear or branched (C1-C7) alkyl group); X represents a hydrogen atom, or one or more substituents selected from a halogen atom, trifluoromethyl, linear or branched (C1-C4) alkyl, and (C1-C4) alkoxy groups; R2 represents a hydrogen atom, or one or more substituents selected from a halogen atom, trifluoromethyl, (C1-C4) alkyl group, or (C1-C4) alkoxy group, or an amino group of the general formula NR3R4 (wherein R3 and R4 each independently represent a hydrogen atom or a (C1-C4) alkyl group, or together with the nitrogen atom they carry, form a pyrrolidine ring, piperidine ring, or morpholine ring, or a phenyl group optionally substituted with an atom or group defined for the above symbol X). The compound of or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is

Chemical formula

[0184] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is of formula VII

Chemical formula

[0185] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [Chemical formula] a compound having the formula of (II) or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is of formula VIII [Chemical formula] [wherein, R 1 is phenyl independently substituted 1 to 5 times with halogen, C1-C3 alkyl, C3-C6 cycloalkyl, OR 9 or SR 10 wherein C1-C3 alkyl and C3-C6 cycloalkyl are optionally substituted 1 to 10 times with R 7 ; R 2 is H; R 3 and R4 are each independently H or CH3; R 5 is (1) hydrogen, (2) C1-C6 alkyl optionally substituted 1 to 11 times with R 7 , (3) gem-dialkyl, and (4) gem-dihalo selected from the group consisting of; or two R 5 substituents on the same carbon, together with the carbon atom to which they are attached, form R 7It may form a 3-, 4- or 5-membered cycloalkyl optionally substituted 1 to 10 times; or Two Rs on adjacent carbons of the ring to which they are attached 5 The substituents, together, may form a 3-, 4-, 5- or 6-membered cycloalkyl optionally substituted 1 to 10 times with R 7 ; R 6 is

Chemical formula

Chemical formula

[0187] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is as follows:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0188] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is [Chemical formula] (ORG-24598) or [Chemical formula] (LY-2365109) a compound having the formula or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is Formula IX [Chemical formula] [wherein, R 1 represents phenyl, or a 5- or 6-membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from O, N or S, wherein the phenyl or heteroaryl is optionally substituted with one or more R 3 ; R 2 represents aryl, a 5- or 6-membered monocyclic heteroaryl, or an 8- to 10-membered bicyclic heteroaryl, the monocyclic or bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from O, N or S, wherein the aryl or heteroaryl is optionally substituted with one or more R 4 ; R 3 is halogen, C 1~4 -alkyl or C3~6 -cycloalkyl, where C 1~4 -alkyl or C 3~6 -cycloalkyl is optionally substituted with one or more halogens; R 4 is halogen, -CN, C 1~4 -alkyl, C 3~6 -cycloalkyl, -C 1~3 -alkyl-C 3~6 -cycloalkyl or -O-C 1~6 alkyl, where C 1~4 -alkyl, C 3~6 -cycloalkyl, -C 1~3 -alkyl-C 3~6 -cycloalkyl or -O-C 1~6 -alkyl is optionally substituted with one or more halogens] a compound of, or a pharmaceutically acceptable salt thereof, or a tautomer or stereoisomer of the compound or a pharmaceutically acceptable salt thereof, or a mixture of any of the foregoing.

[0190] In certain embodiments, the compound of formula IX is of formula IX(a):

Chemical formula

[0191] In certain embodiments, the compound of formula IX is of formula IX(b):

Chemical formula

[0192] In certain embodiments, the compound of formula IX is a compound selected from any of the following, its stereoisomers or mixtures of stereoisomers, or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0193] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is of formula X [Chemical Formula] [wherein] R 1 is a) a 5- or 6-membered monocyclic heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of O, N and S(O)r, b) a 5- or 6-membered monocyclic partially saturated heterocycloalkyl having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, N and S(O)r, and c) a 9- or 10-membered bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, N and S(O) r (wherein r is 0, 1 or 2) selected from the group consisting of; wherein each of said groups a), b) and c) is optionally substituted with one or more substituents independently selected from the group consisting of C -alkyl-, C 1~4 -alkyl-O-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 1~4 -cycloalkyl- and C 3~6 -cycloalkyl-O-, and when substituted, is attached to a nitrogen ring atom, and said substituents are selected from the group consisting of C 3~6 -alkyl-, C 1~4 -alkyl-CO-, C 1~4 -cycloalkyl- and C 3~6 -cycloalkyl-CO-, 3~6 wherein said C -alkyl-, C 1~4 -alkyl-O-, C 1~4 -alkyl-CO-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 1~4 -alkyl-CO-, C 3~6-Cycloalkyl-, C 3~6 -Cycloalkyl-CO- or C 3~6 Each of the substituents of -Cycloalkyl-O- may be substituted by one or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F and -CN; R 2 is hydrogen, C 1~4 -Alkyl-, C 1~4 -Alkyl-O-, -CN and C 3~6 -Cycloalkyl- and is selected from the group consisting of, wherein said C 1~4 -Alkyl-, C 1~4 -Alkyl-O- and C 3~6 -Cycloalkyl group may each be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F and -CN; R 3 is C 1~6 -Alkyl-O-, C 3~6 -Cycloalkyl-O-, morpholino, pyrazolyl, and 4- to 7-membered monocyclic heterocycloalkyl-O- having one oxygen atom as a ring member and optionally O, N and S(O) s (where s = 0, 1 or 2) and is selected from the group consisting of 1 or 2 heteroatoms independently selected from the group consisting of, wherein said C 1~6 -Alkyl-O- and said C 3~6 -Cycloalkyl-O- may each be optionally substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -Alkyl-, C 3~6 -Cycloalkyl-, C 1~6 -Alkyl-O- and C 3~6 -Cycloalkyl-O-; R 4 is hydrogen; or R 3 and R 4together with the ring atoms of the phenyl group to which they are attached, form a 4-, 5- or 6-membered monocyclic partially saturated heterocycloalkyl, or a heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, N and S(O) s (where s = 0, 1 or 2), and may form a heteroaryl, provided that in general formula (I), R 3 is directly bonded to one ring oxygen atom of the ring carbon atoms of the phenyl group to which it is attached; wherein said heterocycloalkyl group may optionally be substituted with 1, 2, 3 or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -alkyl-, C 3~6 -cycloalkyl-, C 1~6 -alkyl-O-, C 3~6 -cycloalkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O- and tetrahydropyranyl-O-; R 5 is hydrogen; R 6 is hydrogen, C 1~4 -alkyl-SO2-, C 3~6 -cycloalkyl-SO2 and -CN; R 7 is hydrogen or a) R 6 and R 7 or b) R 6 and R 5 one of the pair forms, together with the ring atoms of the phenyl group to which they are attached, a 5- or 6-membered partially saturated monocyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, N and S(O) u (where u = 0, 1 or 2), provided that in general formula (I), R 6 is directly bonded to one -SO2- atom of the ring carbon atoms of the phenyl group to which it is attached; Here, the heterocycloalkyl group is optionally substituted with one, two, three or more substituents independently selected from the group consisting of fluoro, -CF3, -CHF2, -CH2F, -CN, C 1~4 -alkyl-, C 1~6 -alkyl-O- and C 3~6 -cycloalkyl-O- and is optionally substituted if necessary] The compound is a compound or a pharmaceutically acceptable salt thereof, or a prodrug of the compound or a pharmaceutically acceptable salt thereof.

[0194] In certain embodiments, the compound of formula X is a compound selected from any of the following, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0195] For example, the compound of formula X can be a mixture of diastereomers or a single diastereomer of any of the following, or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0196] In certain embodiments, the compound of formula X is a compound having the formula

Chem.

[0197] In some embodiments of the methods and uses disclosed herein, the GlyT1 inhibitor is of formula XI

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0198] In certain embodiments, the compound of Formula XI or a pharmaceutically acceptable salt thereof is a compound of Formula XI(a) [Chemical formula] or a pharmaceutically acceptable salt thereof, a compound of Formula XI(b) [Chemical formula] or a pharmaceutically acceptable salt thereof, a compound of Formula XI(c) [Chemical formula] or a pharmaceutically acceptable salt thereof, a compound of Formula XI(d) [Chemical formula] or a pharmaceutically acceptable salt thereof, a compound of Formula XI(e) [Chemical formula] or a pharmaceutically acceptable salt thereof, a compound of Formula XI(f) [Chemical formula] or a pharmaceutically acceptable salt thereof, a compound of Formula XI(g) [Chemical formula] or a pharmaceutically acceptable salt thereof, or a compound of Formula XI(h) [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0199] In certain embodiments, the compound of Formula XI is a compound selected from any of the following, its stereoisomers or mixtures of stereoisomers, or a pharmaceutically acceptable salt thereof. [Chemical formula] [Chemistry] [Chemistry]

[0200] In certain methods and uses disclosed herein, the subject is the subject in need thereof.

[0201] In some embodiments of the uses and methods disclosed herein, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, or a prodrug of a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount.

[0202] In some embodiments, the compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is selected from the compounds described herein. Any of the compounds provided herein can be prepared as a pharmaceutically acceptable salt, solvate or prodrug and / or as part of a pharmaceutical composition described in the patents or patent application publications cited herein.

[0203] The compounds described herein may exhibit a particular stereochemistry, e.g., cis or trans, around certain atoms, but the compounds can also be made in the reverse orientation or as a racemic mixture. Such isomers or racemic mixtures are encompassed by the present disclosure. In addition, although the compounds are presented in a table, any compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, can be selected from the table and used in the embodiments provided herein.

[0204] The compounds described herein can be made according to the methods described in the patents or patent application publications cited herein.

[0205] The compounds can be used to inhibit the GlyT1 transporter. Thus, in some embodiments, the compounds can be referred to as compounds that inhibit the GlyT1 transporter or GlyT1 inhibitors.

[0206] The compounds described herein can be administered in any conventional manner by any route by which they are active. Administration can be systemic, topical, or oral. For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, sublingual or ophthalmic routes, or intravaginal, by inhalation, by depot injection, or by implant, where the implant is of a porous, non-porous or jelly-like material including a membrane such as a silicone membrane or fibers. The method of administration can depend on the target or the condition or disease being treated. The specific choice of route of administration can be selected or adjusted by the clinician according to methods known to the clinician to obtain the desired clinical response.

[0207] In some embodiments, it may be desirable to administer locally to the area in need of treatment one or more compounds, or a pharmaceutically acceptable salt, solvate or prodrug thereof. This can be achieved, for example, but not limited to, by local infusion during surgery, by topical application, for example, in combination with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, where the implant is of a porous, non-porous or jelly-like material including a membrane such as a silicone membrane or fibers.

[0208] The compounds described herein can be administered either alone or in combination with other pharmaceuticals (either together or sequentially). For example, the compounds can be administered in combination with other drugs for the treatment of, for example, hepatic porphyria. Examples of other pharmaceuticals or medicaments are known to those of skill in the art and include, but are not limited to, those described herein.

[0209] Means and methods for administration are known in the art, and the skilled artisan can refer to various pharmacological references for guidance (see, for example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980)).

[0210] The amount of the compound to be administered is a therapeutically effective amount. The dosage to be administered depends on the characteristics of the subject being treated, such as the particular animal being treated, age, weight, health, if any, the type of co-treatment, and the frequency of treatment, and can be readily determined by one of ordinary skill in the art (e.g., by a clinician). Standard dosages for protamine can be used and adjusted (i.e., increased or decreased) according to the above factors. The selection of a specific dosing regimen can be selected, adjusted, or titrated by a clinician according to methods known to the clinician to obtain the desired clinical response.

[0211] The amount of the compounds described herein effective in the treatment and / or prevention of a particular disease, condition or disorder will depend on the nature and extent of the disease, condition or disorder and can be determined by standard clinical techniques. Additionally, in vitro or in vivo assays may be used as needed to assist in identifying the optimal dosage range. The exact dosage to be used in the composition will also depend on the route of administration and the severity of the disorder and should be determined according to the judgment of the practicing physician and the circumstances of each patient. However, suitable dosage ranges for oral administration are generally about 0.001 milligrams to about 200 milligrams per kilogram of body weight, about 0.01 milligrams to about 100 milligrams per kilogram of body weight, about 0.01 milligrams to about 70 milligrams per kilogram of body weight, about 0.1 milligrams to about 50 milligrams per kilogram of body weight, 0.5 milligrams to about 20 milligrams per kilogram of body weight, or about 1 milligram to about 10 milligrams per kilogram of body weight. In some embodiments, the oral dosage is about 5 milligrams per kilogram of body weight.

[0212] In some embodiments, suitable dosage ranges for intravenous (i.v.) administration are about 0.01 mg to about 500 mg per kg of body weight, about 0.1 mg to about 100 mg per kg of body weight, about 1 mg to about 50 mg per kg of body weight, or about 10 mg to about 35 mg per kg of body weight. Suitable dosage ranges for other methods of administration can be calculated based on the aforementioned dosages, as known to those of ordinary skill in the art. For example, recommended dosages for intranasal, transmucosal, intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intracerebral, intravaginal, transdermal administration, or administration by inhalation are in the range of about 0.001 mg to about 200 mg per kg of body weight, about 0.01 mg to about 100 mg per kg of body weight, about 0.1 mg to about 50 mg per kg of body weight, or about 1 mg to about 20 mg per kg of body weight. The effective dosage may be extrapolated from a dose-response curve derived from in vitro or animal model test systems. Such animal models and systems are well known in the art.

[0213] In certain embodiments, the glycine transporter inhibitor administered is a GlyT1 inhibitor, such as a GlyT1 inhibitor disclosed herein. In some embodiments, a suitable dosage range for the GlyT1 inhibitor is from about 5 mg / day to 200 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 5 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 10 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 15 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 20 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 25 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 30 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 35 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 40 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 45 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 50 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 55 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 60 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 65 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 70 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 75 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 80 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 85 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 90 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 95 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 100 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 105 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 110 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 115 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 120 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 125 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 130 mg / day.In some embodiments, the GlyT1 inhibitor is administered at 135 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 140 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 145 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 150 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 155 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 160 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 165 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 170 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 175 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 180 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 185 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 190 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 195 mg / day. In some embodiments, the GlyT1 inhibitor is administered at 200 mg / day.

[0214] In certain embodiments, the glycine transporter inhibitor administered is a GlyT1 inhibitor, such as bitopertin, a pharmaceutically acceptable salt thereof, or a prodrug of bitopertin or a pharmaceutically acceptable salt thereof. In some embodiments, the GlyT1 inhibitor is bitopertin. In some embodiments, a suitable dosage range for bitopertin is from about 5 mg / day to 200 mg / day. In some embodiments, bitopertin is administered at 5 mg / day. In some embodiments, bitopertin is administered at 10 mg / day. In some embodiments, bitopertin is administered at 15 mg / day. In some embodiments, bitopertin is administered at 20 mg / day. In some embodiments, bitopertin is administered at 25 mg / day. In some embodiments, bitopertin is administered at 30 mg / day. In some embodiments, bitopertin is administered at 35 mg / day. In some embodiments, bitopertin is administered at 40 mg / day. In some embodiments, bitopertin is administered at 45 mg / day. In some embodiments, bitopertin is administered at 50 mg / day. In some embodiments, bitopertin is administered at 55 mg / day. In some embodiments, bitopertin is administered at 60 mg / day. In some embodiments, bitopertin is administered at 65 mg / day. In some embodiments, bitopertin is administered at 70 mg / day. In some embodiments, bitopertin is administered at 75 mg / day. In some embodiments, bitopertin is administered at 80 mg / day. In some embodiments, bitopertin is administered at 85 mg / day. In some embodiments, bitopertin is administered at 90 mg / day. In some embodiments, bitopertin is administered at 95 mg / day. In some embodiments, bitopertin is administered at 100 mg / day. In some embodiments, bitopertin is administered at 105 mg / day. In some embodiments, bitopertin is administered at 110 mg / day. In some embodiments, bitopertin is administered at 115 mg / day. In some embodiments, bitopertin is administered at 120 mg / day. In some embodiments, bitopertin is administered at 125 mg / day. In some embodiments, bitopertin is administered at 130 mg / day.In some embodiments, vinpocetine is administered at 135 mg / day. In some embodiments, vinpocetine is administered at 140 mg / day. In some embodiments, vinpocetine is administered at 145 mg / day. In some embodiments, vinpocetine is administered at 150 mg / day. In some embodiments, vinpocetine is administered at 155 mg / day. In some embodiments, vinpocetine is administered at 160 mg / day. In some embodiments, vinpocetine is administered at 165 mg / day. In some embodiments, vinpocetine is administered at 170 mg / day. In some embodiments, vinpocetine is administered at 175 mg / day. In some embodiments, vinpocetine is administered at 180 mg / day. In some embodiments, vinpocetine is administered at 185 mg / day. In some embodiments, vinpocetine is administered at 190 mg / day. In some embodiments, vinpocetine is administered at 195 mg / day. In some embodiments, vinpocetine is administered at 200 mg / day.

[0215] The compounds described herein can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. In some embodiments, the compound can be administered by subcutaneous continuous infusion over a period of about 15 minutes to about 24 hours. Formulations for injection can be present in unit dosage forms, for example, in ampoules or in multi-dose containers, with preservatives added as required. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain formulating agents such as suspending, stabilizing and / or dispersing agents. In some embodiments, the injectable substance is in the form of a short-acting, depot, or implant, and in the form of pellets injected subcutaneously or intramuscularly. In some embodiments, the parenteral dosage form is in the form of a solution, suspension, emulsion, or dry powder.

[0216] For oral administration, the compounds described herein can be formulated by combining the compound with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compound to be formulated as tablets, pills, dragees, capsules, emulsions, solutions, gels, syrups, cachets, pellets, powders, granules, slurries, lozenges, aqueous or oily suspensions, etc. for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained, for example, by adding solid excipients, optionally grinding the resulting mixture, and then treating the mixture of granules, optionally adding suitable auxiliaries, to obtain the core of tablets or dragees. Suitable excipients include, but are not limited to, bulking agents such as sugars including, but not limited to, lactose, sucrose, mannitol and sorbitol; cellulose preparations such as, but not limited to, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and polyvinyl pyrrolidone (PVP). Optionally, disintegrants such as, but not limited to, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or its salts such as sodium alginate can be added.

[0217] Oral compositions can contain one or more optional agents, such as sweeteners, e.g., fructose, aspartame or saccharin; flavoring agents, e.g., peppermint, wintergreen oil, or cherry; coloring agents; and preservatives, to provide pharmaceutically palatable preparations. Also, in the form of tablets or pills, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a prolonged sustained action. Selective permeability membranes surrounding osmotically active driving compounds are also suitable for compounds administered orally. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade.

[0218] The core of the dragee can be provided with a suitable coating. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, as well as suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the coating of the tablets or dragees to identify or characterize different combinations of doses of the active compound.

[0219] Pharmaceutical preparations for oral use can include, but are not limited to, push-fit capsules made of gelatin, as well as sealed soft capsule shells made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in a mixture with bulking agents such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsule shells, the active compound can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin or liquid polyethylene glycol. Additionally, stabilizers can be added.

[0220] For buccal administration, the composition can be in the form of, for example, tablets or lozenges formulated in a conventional manner.

[0221] For administration by inhalation, the compounds described herein can be delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a measured amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated to contain a powdered mixture of the compound and a suitable powder base such as lactose or starch.

[0222] The compounds described herein can also be formulated into rectal compositions, such as suppositories or retention enemas, containing, for example, conventional suppository bases such as cocoa butter or other glycerides. The compounds described herein can also be formulated into vaginal compositions, such as vaginal creams, suppositories, pessaries, vaginal rings, and intrauterine contraceptive devices.

[0223] For percutaneous administration, the compound can be applied to a plaster or, alternatively, by a transdermal therapeutic system that results in delivery to the organism. In some embodiments, the compound is present in or contains creams, solutions, powders, liquid emulsions, liquid suspensions, semi-solids, ointments, pastes, gels, jellies, and foamy substances, or in patches containing any of the foregoing.

[0224] The compounds described herein can be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly), or by intramuscular injection. Depot injections can be administered at intervals of about 1 to about 6 months, or longer. Thus, for example, the compounds can be formulated using suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil), or ion exchange resins, or as poorly soluble derivatives, e.g., as poorly soluble salts.

[0225] In some embodiments, the compound can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng., 1987, 14, 201; Buchwald et al., Surgery, 1980, 88, 507; Saudek et al., N. Engl. J. Med., 1989, 321, 574). In some embodiments, a polymeric material can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger et al., J. Macromol. Sci. Rev. Macromol. Chem., 1983, 23, 61; also see Levy et al., Science, 1985, 228, 190; During et al., Ann. Neurol., 1989, 25, 351; Howard et al., J. Neurosurg., 1989, 71, 105). In yet another embodiment, the controlled release system can be placed in proximity to the target of the compound described herein, such as the liver, and thus only a very small amount of the systemic dose is required (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled release systems discussed in the review by Langer, Science, 1990, 249, 1527-1533 may be used.

[0226] It is also known in the art that the compound can be contained in such a formulation together with pharmaceutically acceptable diluents, extenders, disintegrants, binders, lubricants, surfactants, hydrophobic media, water-soluble media, emulsifiers, buffers, water retention agents, humectants, solubilizers, preservatives, etc. The pharmaceutical composition can also include a suitable solid-phase or gel-phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. In some embodiments, the compounds described herein can be used in combination with agents including, but not limited to, topical analgesics (e.g., lidocaine), barrier devices (e.g., GelClair) or rinsing agents (e.g., Caphosol).

[0227] In some embodiments, the compounds described herein can be delivered in a medium, particularly in liposomes (see Langer, Science, 1990, 249, 1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid, pp. 317-327; generally, see the same book).

[0228] Suitable compositions include, but are not limited to, oral non-absorbable compositions. Suitable compositions also include, but are not limited to, physiological saline, water, cyclodextrin solutions, and buffer solutions with a pH of 3 to 9.

[0229] The compounds described herein, or pharmaceutically acceptable salts, solvates or prodrugs thereof, can be formulated using a number of excipients including, but not limited to, purified water, propylene glycol, PEG400, glycerin, DMA, ethanol, benzyl alcohol, citric acid / sodium citrate (pH3), citric acid / sodium citrate (pH5), tris(hydroxymethyl)aminomethane HCl (pH7.0), 0.9% saline, and 1.2% saline, and any combination thereof. In some embodiments, the excipient is selected from propylene glycol, purified water and glycerin.

[0230] In some embodiments, the formulation can be lyophilized to a solid, for example, and reconstituted with water prior to use.

[0231] When administered to a mammal (e.g., to an animal for veterinary use or to a human for clinical use), the compound can be administered in isolated form.

[0232] When administered to a human, the compound can be sterile. When the compounds of Formulas I-VIII are administered intravenously, water is a suitable carrier. Aqueous saline solutions, as well as aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The composition can also contain, if desired, minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0233] The compositions described herein can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing a liquid, powders, sustained release formulations, suppositories, aerosols, sprays, or any other form suitable for use. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A.R. Gennaro (Editor) Mack Publishing Co.

[0234] In some embodiments, the compounds are formulated as pharmaceutical compositions adapted for administration to humans according to routine procedures. Typically, the compounds are solutions in sterile, isotonic, aqueous buffer. If necessary, the composition can also contain solubilizing agents. Compositions for intravenous administration may optionally contain a local anesthetic, such as lidocaine, to relieve the pain at the site of injection. Generally, the components are supplied either separately or mixed together, in unit dosage form, for example, as a dry lyophilized powder or an anhydrous concentrate in a sealed container, such as an ampoule or sachet, indicating the amount of the active agent. When the compound is administered by infusion, this can be dispensed, for example, in an infusion bottle containing sterile pharmaceutical grade water or saline. When the compound is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the components can be mixed prior to administration.

[0235] The pharmaceutical composition can be in unit dosage form. In such form, the composition can be divided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged preparation, a package containing discrete amounts of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can be a capsule, cachet, or tablet itself, or it can be any of the appropriate number of these packaged forms.

[0236] In some embodiments, the composition is in liquid form, where the active agent (i.e., one of the surface amphiphilic polymers or oligomers disclosed herein) is present in solution, in suspension, as an emulsion, or as a solution / suspension. In some embodiments, the liquid composition is in the form of a gel. In other embodiments, the liquid composition is aqueous. In other embodiments, the composition is in the form of an ointment.

[0237] In some embodiments, the composition is in the form of a solid article. For example, in some embodiments, an ophthalmic composition is a solid article that can be inserted into a suitable location in the eye, such as between the eye and the eyelid or the conjunctival sac, where, for example, as described in U.S. Patent No. 3,863,633; U.S. Patent No. 3,867,519; U.S. Patent No. 3,868,445; U.S. Patent No. 3,960,150; U.S. Patent No. 3,963,025; U.S. Patent No. 4,186,184; U.S. Patent No. 4,303,637; U.S. Patent No. 5,443,505; and U.S. Patent No. 5,869,079, the active agent is released. Release from such articles is typically to the cornea, either via tears that bathe the surface of the cornea or directly to the cornea itself, and the solid article is generally in intimate contact. Solid articles suitable for implantation into the eye in such methods are generally composed primarily of polymers and can be biodegradable or non-biodegradable. Biodegradable polymers that can be used in the preparation of eye implants that carry one or more compounds include, but are not limited to, aliphatic polyesters such as polymers and copolymers of poly(glycolide), poly(lactide), poly(epsilon-caprolactone), poly-(hydroxybutyrate), and poly(hydroxyvalerate), polyamino acids, polyorthoesters, polyanhydrides, aliphatic polycarbonates, and polyether lactones. Suitable non-biodegradable polymers include silicone elastomers.

[0238] The compositions described herein can contain preservatives. Suitable preservatives include, but are not limited to, mercury-containing substances such as phenylmercury salts (e.g., phenylmercury acetate, phenylmercury borate, and phenylmercury nitrate) and thimerosal; stabilized chlorine dioxide; quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride; imidazolidinyl urea; parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben, and their salts; phenoxyethanol; chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol; phenylethyl alcohol; EDTA disodium; and sorbic acid and its salts.

[0239] Optionally, one or more stabilizers can be included in the composition, if necessary, to enhance chemical stability. Suitable stabilizers include, but are not limited to, chelating or complexing agents such as ethylenediaminetetraacetic acid (EDTA), a calcium complexing agent. For example, an appropriate amount of EDTA, or its salt, such as the disodium salt, can be included in the composition to complex excess calcium ions and prevent gel formation during storage. EDTA or its salt can preferably be included in an amount of about 0.01% to about 0.5%. In these embodiments containing preservatives other than EDTA, EDTA or its salt, more specifically, EDTA disodium, can be present in an amount of about 0.025% to about 0.1% by weight.

[0240] One or more antioxidants may also be included in the composition. Suitable antioxidants include, but are not limited to, ascorbic acid, sodium metabisulfite, sodium bisulfite, acetylcysteine, polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, or other agents known to those skilled in the art. Such preservatives are typically used at levels of about 0.001% to about 1.0% by weight.

[0241] In some embodiments, the compound is solubilized, at least in part, by an acceptable solubilizing agent. Certain acceptable nonionic surfactants, such as polysorbate 80, can be useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, such as polyethylene glycol 400 (PEG-400), and glycol ethers.

[0242] A suitable solubilizing agent for solutions and solution / suspension compositions is cyclodextrin. Suitable cyclodextrins can be selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, alkyl cyclodextrins (e.g., methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, diethyl-β-cyclodextrin), hydroxyalkyl cyclodextrins (e.g., hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin), carboxy-alkyl cyclodextrins (e.g., carboxymethyl-β-cyclodextrin), sulfoalkyl ether cyclodextrins (e.g., sulfobutyl ether-β-cyclodextrin), and the like. The ophthalmic applications of cyclodextrins are reviewed in Rajewski et al., Journal of Pharmaceutical Sciences, 1996, 85, 1155-1159.

[0243] In some embodiments, the composition optionally contains a suspending agent. For example, in these embodiments where the composition is an aqueous suspension or solution / suspension, the composition can contain one or more polymers as suspending agents. Useful polymers include, but are not limited to, water-soluble polymers such as cellulose polymers such as hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linked carboxy-containing polymers.

[0244] One or more acceptable pH adjusters and / or buffers can be included in the composition, which include acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in the amounts necessary to maintain the pH of the composition within an acceptable range.

[0245] One or more acceptable salts, solvents or prodrugs can be included in the composition in the amounts necessary to bring the osmotic pressure of the composition within an acceptable range. Such salts include, but are not limited to, those having sodium, potassium or ammonium cations, and chloride, citrate, ascorbic acid, boric acid, phosphoric acid, bicarbonate, sulfate, thiosulfate or bisulfate anions. In some embodiments, salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. In some embodiments, the salt is sodium chloride.

[0246] Optionally, one or more acceptable surfactants, such as, but not limited to, nonionic surfactants, or co-solvents, may be included in the composition to enhance the solubility of the components of the composition, or to impart physical stability, or for other purposes. Suitable nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkyl phenyl ethers, such as octoxynol 10, octoxynol 40; polysorbate 20, 60 and 80; polyoxyethylene / polyoxypropylene surfactants (e.g., Pluronic® F-68, F84 and P-103); cyclodextrin; or other agents known to those skilled in the art. Typically, such co-solvents or surfactants are used in the composition at levels of about 0.01 wt% to about 2 wt%.

[0247] In some embodiments, a pharmaceutical pack or kit is provided that includes one or more containers filled with one or more of the compounds described herein. Optionally, associated with such containers may be a notice in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency for manufacture, use or sale for human administration to treat the conditions, diseases or disorders described herein. In some embodiments, the kit contains more than one of the compounds described herein. In some embodiments, the kit comprises a single injectable dosage form, e.g., a single dose of the compound described herein within an injection device such as a syringe with a needle.

[0248] In some embodiments, the method comprises administering to a subject one or more of the compounds described herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is a subject in need of such treatment. As described herein, in some embodiments, the subject is a mammal, such as, but not limited to, a human.

[0249] In some embodiments, but not limited to, the use in the manufacture of a medicament for the treatment of a method for treating and / or preventing hepatic porphyria or a related syndrome, such as those described herein, including the conditions described herein in a subject, for one or more of the above compounds, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising one or more of the above compounds is also provided. In some embodiments, the subject is a subject in need thereof.

[0250] This embodiment also provides the use of one or more of the above compounds, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising one or more of the above compounds, in the inhibition of the GlyT1 transporter, such as that present on the surface of a cell. In some embodiments, the compound, its pharmaceutically acceptable salt, or its pharmaceutical composition inhibits the internalization, transport and / or degradation of the GlyT1 transporter.

[0251] As used herein, "inhibition" can refer to the inhibition of any specific activity. The activity of the GlyT1 transporter can be measured by any method known in the art, including but not limited to the methods described herein.

[0252] The compounds described herein are inhibitors of the GlyT1 transporter. The ability of a compound to inhibit GlyT1 transporter activity can be measured using any assay known in the art.

[0253] Generally, assays for testing compounds that inhibit GlyT1 transporter activity involve determining any parameter, either indirectly or directly, under the influence of the GlyT1 transporter, such as a functional, physical, or chemical effect.

[0254] A sample or assay containing the GlyT1 transporter treated with a potential inhibitor is compared to a control sample without the inhibitor to examine the degree of inhibition. The control sample (untreated with the inhibitor) is assigned a relative GlyT1 transporter activity value of 100%. Inhibition of the GlyT1 transporter is achieved when the GlyT1 transporter activity value relative to the control is approximately 80%, 50%, or 25%.

[0255] Ligand binding to the GlyT1 transporter can be tested in several formats. Binding can occur in solution, in a bilayer membrane, bound to a solid phase, in a lipid monolayer, or in a vesicle. For example, in an assay, the binding of a natural ligand to its transporter is measured in the presence of a candidate modulator, such as a compound described herein. Alternatively, the binding of a candidate modulator can be measured in the presence of a natural ligand. In many cases, a competition assay that measures the ability of a compound to compete with the binding of a natural ligand to the transporter is used. Binding can be tested, for example, by measuring changes in spectroscopic properties (e.g., fluorescence, absorption, refractive index), hydrodynamic (e.g., shape) changes, or changes in chromatographic or solubility properties.

[0256] After the transporter is expressed in the cells, the cells can grow in an appropriate medium in an appropriate cell plate. The cells can be seeded, for example, at 5000 - 10000 cells per well in a 384-well plate. In some embodiments, the cells are seeded at about 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, or 10000 cells per well. The plate can have any number of wells, and the number of cells can be modified accordingly.

[0257] Any pharmaceutical having utility in the applications described herein can be used in combination therapy, co - administration or co - formulation with the above - described compositions. Thus, the compounds described herein can be administered either before, together with, or after such therapeutic agents are administered to a subject.

[0258] Additional pharmaceuticals can be administered in combination therapy (including co - formulations) with one or more compounds described herein.

[0259] In some embodiments, the response of the disease or disorder to treatment is monitored and the treatment regimen is adjusted as needed taking such monitoring into account.

[0260] The frequency of administration typically is such that the period between doses, e.g., between one dose and the next during waking hours, is about 1 to about 24 hours, about 2 to about 12 hours, about 3 to about 8 hours, or about 4 to about 6 hours. In some embodiments, the dose is administered 1, 2, 3, or 4 times a day. Appropriate dosing intervals depend in part on the length of time the selected composition can maintain the concentration of the compound in the subject and / or target tissue (e.g., above the EC 50 (minimum concentration of the compound that inhibits the activity of the transporter by 90%)), which will be understood by those skilled in the art. Ideally, the concentration remains above the EC 50 for at least 100% of the dosing interval. If this is not achievable, the concentration should remain above the EC 50 for at least about 60% of the dosing interval or desirably remain above the EC 50 for at least about 40% of the dosing interval.

[0261] Method of Use The present application provides a method for preventing or treating hepatic porphyria in a subject, the method comprising administering to the subject one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors or pharmaceutically acceptable salts thereof. In certain embodiments, the glycine transporter inhibitor is a GlyT1 inhibitor, such as a GlyT1 inhibitor disclosed herein. For example, the present application provides a method for preventing, treating, or reducing the rate of progression and / or severity of hepatic porphyria in a subject, the method comprising administering to the subject

Chemical formula

[0262] In part, the present disclosure relates to a method for treating hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, the present disclosure relates to a method for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof.

[0263] In some embodiments, hepatic porphyria is acute hepatic porphyria. In some embodiments, hepatic porphyria is non-acute hepatic porphyria. In some embodiments, hepatic porphyria is acute intermittent porphyria (AIP). In some embodiments, hepatic porphyria is ALA dehydratase porphyria (ADP). In some embodiments, hepatic porphyria is variegate porphyria (VP). In some embodiments, hepatic porphyria is hereditary coproporphyria (HCP). In some embodiments, hepatic porphyria is hydroxymethylbilane synthase porphyria. In some embodiments, hepatic porphyria is late-onset cutaneous porphyria (PCT). In some embodiments, PCT is familial or sporadic PCT. In some embodiments, hepatic porphyria is myeloproliferative hepatic porphyria (HEP).

[0264] The terms "subject", "individual" or "patient" are interchangeable throughout this specification and refer to either a human or a non-human animal. These terms include mammals such as humans, non-human primates, laboratory animals, domestic animals (including cows, pigs, camels, etc.), companion animals (e.g., dogs, cats, other pet animals, etc.) and rodents (e.g., mice and rats). In certain embodiments, the patient, subject or individual is human.

[0265] This application provides a method for preventing, treating, or reducing the rate of progression and / or severity of hepatic porphyria, the method comprising administering to a subject one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors or pharmaceutically acceptable salts thereof. In some embodiments, the one or more glycine transporter inhibitors are one or more GlyT1 and / or GlyT2 inhibitors. In some embodiments, the one or more glycine transporter inhibitors are one or more GlyT1 inhibitors, such as one or more GlyT1 inhibitors disclosed herein. In certain specific embodiments described above, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. For example, this application provides a method for preventing, treating, or reducing the rate of progression and / or severity of hepatic porphyria in a subject, the method comprising administering to the subject vitopeltine or a pharmaceutically acceptable salt thereof, or a prodrug of vitopeltine or a pharmaceutically acceptable salt thereof.

[0266] This application further provides the use of one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors or pharmaceutically acceptable salts thereof, in the manufacture of a formulation for the treatment of hepatic porphyria in a subject. In some embodiments, the one or more glycine transporter inhibitors are one or more GlyT1 and / or GlyT2 inhibitors. In some embodiments, the one or more glycine transporter inhibitors are one or more GlyT1 inhibitors, such as one or more GlyT1 inhibitors disclosed herein. In certain such embodiments, the GlyT1 inhibitor is vitopeltine or a pharmaceutically acceptable salt thereof, or a prodrug of vitopeltine or a pharmaceutically acceptable salt thereof. In certain specific embodiments described above, the formulation is administered in a therapeutically effective amount.

[0267] Hepatic porphyria Porphyrias include eight hereditary metabolic disorders of heme biosynthesis in which various enzymes in the complex heme biosynthetic pathway are disrupted. Porphyrias are broadly classified as acute vs. non-acute or hepatic vs. erythropoietic porphyrias based on their clinical presentation. Acute hepatic porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and aminolevulinate dehydratase deficiency porphyria (ADP), which often lead to severe abdominal, psychopathological, neurological, or cardiovascular symptoms. AIP, HCP, and VP are autosomal dominant porphyrias, and ADP is an autosomal recessive porphyria. In rare cases, AIP, HCP, and VP occur as homozygous dominant forms. Porphyria cutanea tarda (PCT) is a non-acute hepatic porphyria, and its patients often present with herpes, blisters, milia, and hirsutism on the cheeks, temples, and eyebrows. In addition, there is a rare homozygous recessive form of PCT known as hepatoerythropoietic porphyria (HEP). The clinical and laboratory features of these porphyrias are described in Table 1 below.

Table 1

[0268] Porphyria is a family of hereditary or acquired disorders resulting from the deficient activity of specific enzymes in the heme biosynthetic pathway, also referred to herein as the porphyrin pathway. Porphyrins are the major precursors of heme. Porphyrins and porphyrin precursors include 5-aminolevulinic acid (ALA), porphobilinogen (PBG), hydroxymethylbilane (HMB), uroporphyrinogen I or III, coproporphyrinogen I or III, protoporphyrinogen IX, and protoporphyrin IX. Heme is an essential moiety of hemoglobin, myoglobin, catalase, peroxidase, and cytochrome, the latter including respiratory and P450 liver cytochromes. Heme is synthesized in most or all human cells. Approximately 85% of heme is made in erythroid cells, mainly for hemoglobin. Most of the remaining heme is made in the liver, 80% of which is used for cytochrome synthesis. Deficiency of specific enzymes in the porphyrin pathway leads to insufficient heme production and also to the accumulation of porphyrin precursors and / or porphyrins which, at high concentrations, can be toxic to cell or organ function.

[0269] Porphyria can be classified according to the primary site of overproduction and accumulation of porphyrin or its precursors. In hepatic porphyria, porphyrins and porphyrin precursors are mainly overproduced in the liver, while in erythropoietic porphyria, porphyrins are overproduced in the bone by erythroid cells. Acute or hepatic porphyria can lead to neurological dysfunctions and neurological signs that affect both the central and peripheral nervous systems, such as pain (e.g., abdominal pain and / or chronic neuropathic pain), vomiting, neuropathy (e.g., acute neuropathy, progressive neuropathy), muscle weakness, seizure, mental disorders (e.g., hallucination, depression, anxiety, delusional disorder), cardiac arrhythmia, tachycardia, constipation, and diarrhea. Cutaneous or erythropoietic porphyria mainly affects the skin and causes symptoms such as painful photosensitivity, herpes, necrosis, pruritus, swelling, and increased hair growth in areas such as the forehead. Subsequent infections of skin lesions can lead to not only bone and tissue loss but also scarring, disfigurement, and loss of fingers (e.g., fingers, toes). Most porphyrias are caused by mutations encoding enzymes in the heme biosynthetic pathway.

[0270] Not all porphyrias are hereditary. For example, patients with liver diseases may develop porphyria as a result of liver dysfunction. Patients with PCT may acquire a deficient activity of uroporphyrinogen decarboxylase (URO-D) due to the formation of ORO-D enzyme that is lower than normal enzyme activity.

[0271] Acute intermittent porphyria (AIP), also known as porphobilinogen (PBG) deaminase deficiency or hydroxymethylbilane synthase (HMBS) deficiency, is the most common type of acute hepatic porphyria. Other types of acute hepatic porphyria include hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA dehydratase deficiency porphyria (ADP). Non-acute hepatic porphyria includes porphyria cutanea tarda (PCT), a disease in which patients often present with herpes, blisters, milia, and hirsutism on the cheeks, temples, and eyebrows. In addition, there is a rare homozygous recessive form of PCT known as hepatoerythropoietic porphyria (HEP). The clinical and laboratory characteristics of these porphyrias are described in Table 1.

[0272] AIP has been found to have a prevalence of about 1 in 10,000 in certain populations (e.g., in northern Sweden). The prevalence of mutations in the general population in Europe, excluding the United States and the United Kingdom, is estimated to be about 1 in 10,000 to 1 in 20,000. Clinical disease appears in only approximately 10 - 15% of individuals with mutations known to be associated with AIP. However, the penetrance is about 40% in individuals with certain mutations (e.g., the W198X mutation). AIP is typically latent before puberty. Symptoms are more common in women than in men. The prevalence of the disease is probably underestimated due to its incomplete penetrance and long latency period. In the United States, it is estimated that there are about 2000 patients who have suffered at least one attack. In France, Sweden, the United Kingdom, and Poland, there are an estimated 150 active relapse cases, and these patients have a median age of 30 years and are mainly young women.

[0273] AIP affects, for example, the visceral, peripheral, autonomic, and central nervous systems. The symptoms of AIP are variable and include gastrointestinal symptoms (e.g., severe and poorly localized abdominal pain, nausea / vomiting, constipation, diarrhea, ileus), urinary symptoms (urinary retention, urinary incontinence / retention, or dark urine), neurological symptoms (e.g., sensory neuropathy, motor neuropathy (e.g., affecting cranial nerves and / or leading to weakness in the arms or legs), seizures, neuropathic pain (e.g., pain associated with progressive neuropathy, e.g., chronic neuropathic pain), neuropsychiatric symptoms (e.g., confusion, anxiety, agitation, hallucinations, hysteria, delirium, affective blunting, depression, phobia, psychosis, insomnia, somnolence, stupor), autonomic involvement (e.g., cardiovascular symptoms, e.g., tachycardia, hypertension, and / or arrhythmias, as well as other symptoms, e.g., increased circulating catecholamine levels, sweating, restlessness, and / or tremors), dehydration, and electrolyte abnormalities. The most common symptoms are abdominal pain and tachycardia. In addition, patients frequently have chronic neuropathic pain and develop progressive neuropathy. Patients with recurrent attacks often have prodromal symptoms. Persistent paralysis may occur after severe attacks. Recovery from severe attacks that are not treated promptly can take weeks or months. Acute attacks can be fatal, for example, due to respiratory muscle paralysis or cardiovascular failure from electrolyte disturbances. Before the availability of hemin treatment, up to 20% of patients with AIP died from this disease.

[0274] Individuals with the gene for AIP have an increased risk of hepatocellular carcinoma. In those with recurrent attacks, the risk of hepatocellular carcinoma is particularly significant, and after the age of 50, the risk is approximately 100 times higher than in the general population.

[0275] Attacks of acute porphyria can be induced by endogenous or exogenous factors. Such factors can induce attacks by, for example, increasing the demand for hepatic P450 enzymes and / or inducing ALAS1 activity in the liver. An increase in the demand for hepatic P450 enzymes results in a decrease in hepatic free heme, thereby inducing the synthesis of hepatic ALAS1.

[0276] As exacerbating factors, there are starvation (or other forms of reduced or inappropriate calorie intake due to emergency dieting, long-distance sports competitions, etc.), metabolic stress (e.g., infectious diseases, surgery, international air travel, and psychological stress), endogenous hormones (e.g., progesterone), smoking, fat-soluble foreign chemicals (e.g., chemicals present in tobacco smoke, certain prescription drugs, organic solvents, biocides, components in alcoholic beverages), and endocrine factors (e.g., reproductive hormones (women may experience exacerbation during the premenstrual period), synthetic estrogens, progesterone, ovulation-inducing substances, and hormone replacement therapy).

[0277] For example, more than 1000 drugs including alcohol, barbiturates, carbamazepine, carisoprodol, clonazepam (high doses), danazol, diclofenac and possibly other NSAIDs, ergot, estrogen, ethchlorvynol, glutethimide, griseofulvin, mephenytoin, meprobamate (also mebutamate and tibutamate), meprilone, metoclopramide, phenytoin, primidone, progesterone and synthetic progestins, pyrazinamide, pyrazolone (aminopyrine and antipyrine), rifampin, succinimide (ethosuximide and methsuximide), sulfonamide antibiotics, and valproic acid are contraindicated in acute hepatic porphyrias (e.g., AIP, HCP, ADP, and VP).

[0278] Objective signs of AIP include urine discoloration during acute attacks (the urine may appear red or reddish-brown), and increased concentrations of PBG and ALA in urine during acute attacks. Molecular genetic testing identifies mutations in the PBG deaminase (also known as HMBS) gene in more than 98% of affected individuals.

[0279] The differential diagnosis of porphyria can involve determining the type of porphyria by measuring the individual levels of porphyrins or porphyrin precursors (e.g., ALA, PBG) in urine, feces, and / or plasma during an attack (e.g., by chromatography and fluorometry). The diagnosis of AIP can be confirmed by establishing that the erythrocyte PBG deaminase activity is 50% or less of normal levels. DNA testing for mutations can be performed in patients and at-risk family members. The diagnosis of AIP is typically confirmed by DNA testing to identify specific causative gene mutations (e.g., HMBS mutations).

[0280] Treatment of acute attacks typically requires hospitalization to manage and treat acute symptoms, including, for example, abdominal pain, seizure attacks, dehydration / hypo - natremia, nausea / vomiting, tachycardia / high blood pressure, and urinary retention / ileus. For example, abdominal pain can be treated with, for example, narcotic analgesics, seizure attacks can be treated with seizure precautions and possibly drug therapy (although many anti - seizure drug therapies are contraindicated), nausea / vomiting can be treated with, for example, phenothiazines, and tachycardia / high blood pressure can be treated with, for example, beta - blockers. Treatment can include withdrawal of dangerous drug therapies, monitoring of respiratory function, and muscle strength and neurological status. Mild attacks (e.g., those without flaccid paralysis or hyponatremia) can be treated with at least 300 g of intravenous 10% glucose per day, although hemin is increasingly being provided promptly. Severe attacks must be treated as soon as possible with intravenous hemin (3 - 4 mg / kg per day for 4 - 14 days) and intravenous glucose while waiting for IV hemin to take effect. Typically, attacks are treated with 4 days of IV hemin and IV glucose while waiting for the administration of IV hemin.

[0281] Hemin (Panhematin® or hemin for injection, formerly known as hematin) is the only heme product approved for use in the United States and was the first drug approved under the Orphan Drug Act. Panhematin® is hemin derived from processed red blood cells (PRBCs) and is protoporphyrin IX containing ferric ions (heme B) and chloride ligands. Heme acts to limit the hepatic and / or bone marrow synthesis of porphyrins. The exact mechanism by which hemin produces symptomatic improvement in patients with acute episodes of hepatic porphyria has not been elucidated, but its effect may be due to (feedback) inhibition of δ-aminolevulinic acid (ALA) synthase, an enzyme that limits the rate of the porphyrin / heme biosynthetic pathway. Inhibition of ALA synthase should result in reduced production of ALA and PBG, as well as porphyrins and porphyrin intermediates.

[0282] Disadvantages of hemin include its delayed effect on clinical symptoms and its inability to prevent recurrence of attacks. Adverse reactions associated with hemin administration can include thrombophlebitis, anticoagulation, thrombocytopenia, renal failure, or iron overload, which is particularly likely in patients who require multiple courses of hemin treatment for recurrent attacks. An indwelling intravenous catheter is required for access in patients with recurrent attacks to prevent phlebitis. Rarely reported side effects include fever, pain, malaise, hemolysis, anaphylaxis, and circulatory collapse.

[0283] Heme is difficult to prepare in a stable form for intravenous administration. It is insoluble at neutral pH but can be prepared as heme hydroxide at pH 8 or higher. Panhematin® is a lyophilized hemin preparation. Lyophilized hemin, when solubilized for intravenous administration, rapidly forms degradation products that cause transient anticoagulant effects and phlebitis at the injection site. Heme albumin and heme arginate (Normosang, the European version of hemin) are more stable and may be less likely to cause thrombophlebitis. However, heme arginate is not approved for use in the United States. Panhemin® can be stabilized by solubilizing it in 30% human albumin rather than sterile water, but albumin has the added effect of expanding the intravascular volume, increasing the cost of treatment, and being isolated from human blood, thus increasing the risk of pathogens.

[0284] Successful treatment of an acute attack does not prevent recurrence or delay it. There is a question as to whether hemin itself can induce recurrent attacks due to induction of heme oxygenase. Nevertheless, in some regions (particularly France), young women with increased recurrent attacks are being treated weekly with hemin in an attempt to achieve prevention.

[0285] Givosiran (Givlaari®), a small interfering ribonucleic acid (siRNA) against aminolevulinate synthase 1, is also used to treat patients with acute hepatic porphyria by using RNA interference to target and degrade ALAS1 mRNA in hepatocytes. Suspected risks associated with the use of givosiran include anaphylactic reactions, hepatotoxicity, and nephrotoxicity. For example, 15% of patients in givosiran clinical trials showed an increase in transaminase (ALT) levels three times the upper limit of normal. In addition, 15% of patients who received givosiran had kidney-related adverse reactions, including an increase in serum creatinine levels and a decrease in estimated glomerular filtration rate.

[0286] Limited experience with liver transplantation, when successful, suggests that it is an effective treatment for AIP. In human patients, there have been approximately 12 transplants in Europe with various effects, with a therapeutic effect. Liver transplantation can restore normal excretion of ALA and PBG and prevent acute attacks. Furthermore, when the liver of a patient with AP is transplanted into another patient ("domino transplantation"), the recipient of the transplant can develop AIP. Orthotopic liver transplantation is curative, but this procedure has significant morbidity and mortality, and the availability of liver donors is limited.

[0287] Among the long-term clinical effects of acute porphyrias, chronic neuropathic pain can result from a progressive neuropathy due to neurotoxic effects, such as those of elevated porphyrin precursors (e.g., ALA and / or PBG). Patients may suffer from neuropathic pain before or during an acute attack. Older patients may experience an increase in neuropathic pain with age, and for this reason, various narcotics are typically prescribed. Electromyogram abnormalities and decreased conduction times have been identified in patients with acute hepatic porphyria. In patients with acute porphyrias (e.g., ADP, AIP, HCP, or VP), the levels of porphyrin precursors (ALA and PBG) are often elevated in asymptomatic patients and symptomatic patients between attacks. Therefore, reduction of porphyrin precursors and restoration of normal heme biosynthesis by reducing the level of ALAS1 expression and / or activity are expected to prevent and / or minimize the development of chronic and progressive neuropathy. Treatments, such as chronic treatments (e.g., regular treatments with iRNAs as described herein, e.g., treatments according to the dosing regimens described herein, e.g., weekly or bi-weekly treatments), can continuously reduce ALAS1 expression in patients with acute porphyrias having elevated levels of porphyrin precursors, porphyrins, porphyrin products, or their metabolites. Such treatments may be provided as necessary to prevent, or reduce the frequency or severity of, the symptoms (e.g., pain and / or neuropathy) of an individual patient and / or to reduce the levels of porphyrin precursors, porphyrins, porphyrin products, or metabolites.

[0288] There is a need to identify novel therapies that can be used for the treatment of porphyrias. As discussed above, existing treatments such as hemin, gibostirane, and liver transplantation have a number of drawbacks. For example, the effect of hemin on clinical symptoms is slow, it is expensive, and it can have side effects (e.g., thrombophlebitis, anticoagulation, thrombocytopenia, iron overload, kidney failure).

[0289] Treatment of Hepatic Porphyrias In some embodiments, the present disclosure provides a method for preventing or treating hepatic porphyria in a subject, the method comprising administering to the subject one or more glycine transporter inhibitors or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors or pharmaceutically acceptable salts thereof. In certain embodiments, the glycine transporter inhibitor is a GlyT1 inhibitor, such as a GlyT1 inhibitor disclosed herein.

[0290] In some embodiments, the subject has or is at risk of developing hepatic porphyria (e.g., AIP, HCP, VP, ADP, PCT, and HEP). In some embodiments, the hepatic porphyria is acute hepatic porphyria (e.g., AIP, HCP, VP, and ADP). In some embodiments, the hepatic porphyria is non-acute hepatic porphyria (e.g., PCT and HEP). In some embodiments, the hepatic porphyria is dual hepatic porphyria, e.g., at least two hepatic porphyrias. In some embodiments, the dual hepatic porphyria comprises two or more hepatic porphyrias selected from the group consisting of AIP, HCP, VP, ADP, PCT, and HEP.

[0291] In some embodiments, the hepatic porphyria is caused by a heterozygous mutation that results in reduced enzyme activity. In some embodiments, the hepatic porphyria is caused by a homozygous mutation that results in reduced enzyme activity. In some embodiments, the hepatic porphyria is an autosomal recessive disorder (e.g., ADP). In some embodiments, the subject has a genetic alteration (e.g., a mutation) described herein but is otherwise asymptomatic.

[0292] Mutations associated with hepatic porphyrias include mutations in genes encoding certain enzymes in the heme biosynthetic pathway (porphyrin pathway), or genes that alter the expression of genes in the heme biosynthetic pathway (e.g., ALAD, HMBS, UROD, UROS, CPOX, and PPOX). In many embodiments, the subject has one or more mutations in an enzyme of the porphyrin pathway (e.g., ALA-dehydratase, PBG deaminase, uroporphyrinogen III synthase, uroporphyrinogen III synthase, uroporphyrinogen decarboxylase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase).

[0293] In some embodiments, patients with acute hepatic porphyria (e.g., AIP), or patients who have mutations associated with acute hepatic porphyria (e.g., AIP) but are asymptomatic, have elevated ALA and / or PBG levels compared to healthy individuals. In such cases, the levels of ALA and / or PBG can be elevated even if the patient is not having, or has never had, an attack. In some such cases, the patient is otherwise completely asymptomatic. In some such cases, the patient may suffer from neuropathic pain, such as chronic pain (e.g., chronic neuropathic pain). In some cases, the patient has neuropathy. In some cases, the patient has progressive neuropathy.

[0294] In some embodiments, the subject has an acute attack of hepatic porphyria. In some embodiments, the subject has a non-acute attack of hepatic porphyria. In some embodiments, the subject has not yet experienced an acute attack of hepatic porphyria. In some embodiments, the subject is suffering from chronic pain. In some embodiments, the subject has nerve damage. In some embodiments, the subject has EMG changes and / or changes in nerve conduction velocity. In some embodiments, the subject is asymptomatic. In some embodiments, the subject is at risk of developing hepatic porphyria (e.g., has a genetic mutation associated with hepatic porphyria) and is asymptomatic. In some embodiments, the subject has previously had an acute attack of hepatic porphyria but is asymptomatic at the time of treatment.

[0295] In some embodiments, the subject is at risk of developing hepatic porphyria and is prophylactically treated to prevent the development of hepatic porphyria. In some embodiments, the subject has elevated levels of porphyrin or porphyrin precursors (e.g., ALA and / or PBG). In some embodiments, prophylactic treatment begins at puberty. In some embodiments, the treatment reduces the levels (e.g., plasma levels or urinary levels) of porphyrin or porphyrin precursors (e.g., ALA and / or PBG). In some embodiments, the treatment prevents the occurrence of elevated levels of porphyrin or porphyrin precursors (e.g., ALA and / or PBG). In some embodiments, the treatment prevents the occurrence of symptoms associated with hepatic porphyria (e.g., pain or nerve damage) or reduces their frequency or severity.

[0296] In some embodiments, the subject treated according to the methods described suffers from pain, e.g., chronic pain. In some embodiments, the method is effective in treating pain (e.g., by reducing the severity of the pain or curing the pain). In some embodiments, the method is effective in reducing or preventing nerve damage.

[0297] In some embodiments, the subject to be treated according to the methods described herein has (a) elevated levels of ALA and / or PBG and (b) suffers from pain (e.g., chronic pain). In some embodiments, the methods are effective to reduce elevated levels of ALA and / or PBG and / or to treat pain (e.g., by reducing the severity of pain or curing the pain).

[0298] In some embodiments, the subject is a subject suffering from one or more acute episodes of one or more hepatic porphyria symptoms. In other embodiments, the subject is a subject chronically suffering from one or more symptoms of hepatic porphyria (e.g., pain, e.g., neuropathic pain and / or neuropathy, e.g., progressive neuropathy). In some embodiments, the subject to be treated according to the methods described herein has recently experienced or is currently experiencing prodromal symptoms.

[0299] "Prodromal symptoms", as used herein, include any symptoms that an individual subject has previously experienced immediately prior to the occurrence of an acute attack. Typical symptoms of prodromal symptoms include, for example, abdominal pain, nausea, headache, psychological symptoms (e.g., anxiety), restlessness and / or insomnia. In some embodiments, the subject experiences pain (e.g., abdominal pain and / or headache) during the prodromal symptoms. In some embodiments, the subject experiences nausea during the prodromal symptoms. In some embodiments, the subject experiences psychological symptoms (e.g., anxiety) during the prodromal symptoms. In some embodiments, the subject becomes restless and / or suffers from insomnia during the prodromal symptoms.

[0300] An acute "attack" of hepatic porphyria typically includes the onset of one or more symptoms of hepatic porphyria in a patient having a mutation associated with hepatic porphyria (e.g., a mutation in a gene encoding an enzyme in the porphyrin pathway).

[0301] In some embodiments, the GlyT1 inhibitor is administered after an acute attack of hepatic porphyria. In some embodiments, the GlyT1 inhibitor is administered during an acute attack of hepatic porphyria. In some embodiments, administration of the GlyT1 inhibitor is effective to reduce the severity of the attack (e.g., by reversing one or more signs or symptoms associated with the attack). In some embodiments, administration of the GlyT1 inhibitor is effective to shorten the duration of the attack. In some embodiments, administration of the GlyT1 inhibitor is effective to stop the attack. In some embodiments, the GlyT1 inhibitor is administered prophylactically to prevent an acute attack of hepatic porphyria. In some embodiments, prophylactic administration is before, during, or after exposure to or appearance of a worsening factor. In some embodiments, the subject is at risk of developing porphyria.

[0302] As used herein, "worsening factor" refers to an endogenous or exogenous factor that can induce an acute attack of one or more symptoms associated with porphyria. Worsening factors include starvation (or other forms of reduced or inappropriate caloric intake due to, e.g., crash diets, long-distance athletic competitions), metabolic stress (e.g., infections, surgery, international air travel, and psychological stress), endogenous hormones (e.g., progesterone), smoking, lipophilic xenobiotics (e.g., chemicals present in tobacco smoke, certain prescription drugs, organic solvents, biocides, components in alcoholic beverages), endocrine factors (e.g., reproductive hormones (women may experience exacerbation during the premenstrual period), synthetic estrogens, progesterone, ovulation-inducing substances, and hormone replacement therapy), and lead. Other common worsening factors include drugs that induce cytochrome P450 and phenobarbitol.

[0303] In some embodiments, the GlyT1 inhibitor is administered during the prodromal symptoms. In some embodiments, the prodromal symptoms are characterized by pain (e.g., headache and / or abdominal pain), nausea, psychological symptoms (e.g., anxiety), restlessness and / or insomnia. In some embodiments, the GlyT1 inhibitor is administered during a specific stage of the menstrual cycle, e.g., during the luteal phase.

[0304] In some embodiments, the administration of the GlyT1 inhibitor is effective in preventing seizures (e.g., recurrent seizures associated with prodromal symptoms and / or exacerbating factors, e.g., a specific stage of the menstrual cycle, e.g., the luteal phase). In some embodiments, the administration of the GlyT1 inhibitor is effective in reducing the frequency of seizures. In some embodiments, the administration of the GlyT1 inhibitor is effective in reducing the severity of seizures (e.g., by reversing one or more signs or symptoms associated with the seizure). In some embodiments, the administration of the GlyT1 inhibitor is effective in shortening the duration of seizures. In some embodiments, the administration of the GlyT1 inhibitor is effective in stopping seizures.

[0305] In some embodiments, the administration of the GlyT1 inhibitor is effective in preventing pain, e.g., neuropathic pain, or reducing its frequency or severity. In some embodiments, the administration of the GlyT1 inhibitor is effective in preventing neuropathy, or reducing its frequency or severity. In some embodiments, the subject has or is at risk of developing hepatic porphyria and suffers from pain (e.g., neuropathic pain, e.g., chronic neuropathic pain) or neuropathy (e.g., progressive neuropathy). In some embodiments, the subject has elevated levels of ALA and / or PBG and suffers from chronic pain.

[0306] The effects of administering a GlyT1 inhibitor can be established, for example, by comparison with an appropriate control. For example, a decrease in the frequency of acute attacks and a decrease in the level of one or more porphyrins or porphyrin precursors may be established as a decrease in frequency compared to an appropriate control group, for example, in a group of patients with AIP. As a control group (e.g., a group of similar individuals or the same group of individuals in a crossover design), for example, an untreated population, a population treated with a conventional treatment for hepatic porphyria (e.g., conventional treatments for AIP include glucose, hemin, or both); a population treated with a placebo, or, optionally, a GlyT1 inhibitor in combination with one or more conventional treatments for hepatic porphyria (e.g., glucose, e.g., IV glucose) may be mentioned.

[0307] A "risky" subject for developing hepatic porphyria, as used herein, is a subject having a family history of hepatic porphyria and / or a medical history of one or more recurrent or chronic hepatic porphyria symptoms, and / or a subject having a genetic alteration (e.g., a mutation) in a gene encoding an enzyme of the heme biosynthetic pathway, and a subject having a genetic alteration, e.g., a mutation known to be associated with hepatic porphyria.

[0308] In some embodiments, the alteration, e.g., the mutation, renders the individual sensitive to acute attacks (e.g., upon exposure to a worsening factor, e.g., a drug, diet, or other worsening factor, e.g., a worsening factor disclosed herein). In some embodiments, the alteration, e.g., the mutation, is associated with elevated levels of porphyrins or porphyrin precursors (e.g., ALA and / or PBG). In some embodiments, the alteration, e.g., the mutation, is associated with chronic pain (e.g., chronic neuropathic pain) and / or neuropathy (e.g., progressive neuropathy). In some embodiments, the alteration, e.g., the mutation, is associated with changes in EMG and / or nerve conduction velocity.

[0309] In some embodiments, the alteration is a mutation in a gene selected from the group consisting of ALAD, HMBS, UROD, CPOX, and PPOX. In some embodiments, the alteration is an alteration, e.g., a mutation, in a gene encoding an enzyme in the heme biosynthetic pathway. In some embodiments, the subject has a genetic alteration but does not suffer from an acute attack. In some embodiments, the subject has a mutation associated with AIP, HCP, VP, ADP, PCT, or HEP.

[0310] In some embodiments, hepatic porphyria is AIP. In some such embodiments, the subject has an alteration in PBGD (the gene encoding PBG deaminase), e.g., at least one mutation. Many PBGD mutations are known in the art. In some embodiments, the subject is heterozygous for the PBGD mutation. In other embodiments, the subject is homozygous for the PBGD mutation. A homozygous subject can have two identical or two different mutations in the PBGD gene. In some embodiments, hepatic porphyria is HCP. In some embodiments, the subject has an alteration in CPOX (i.e., the gene encoding the enzyme coproporphyrinogen III oxidase), e.g., at least one mutation. In some embodiments, hepatic porphyria is VP. In some embodiments, the subject has an alteration in PPOX (i.e., the gene encoding protoporphrinogen oxidase), e.g., at least one mutation. In some embodiments, hepatic porphyria is ADP (e.g., autosomal recessive ADP). In some embodiments, the subject has an alteration in ALAD (the gene encoding ALA dehydratase), e.g., at least one mutation. In some embodiments, hepatic porphyria is PCT. In some embodiments, the subject has an alteration in UROD (the gene encoding uroporphyrinogen decarboxylase), e.g., at least one mutation. In some embodiments, hepatic porphyria is CEP. In some embodiments, the subject has an alteration in UROS (the gene encoding uroporphyrinogen III synthase), e.g., at least one mutation.

[0311] In some embodiments, the increased levels of porphyrin precursors are due to lead poisoning. Lead poisoning inhibits the activity of each of ALAD, CPOX, and FECH, which are enzymes involved in heme biosynthesis. Patients with lead poisoning are frequently misdiagnosed with ADP or other acute porphyrias. In some embodiments, a subject with lead poisoning has decreased enzyme activity of ALAD. In some embodiments, a subject with lead poisoning has decreased enzyme activity of CPOX. In some embodiments, a subject with lead poisoning has decreased enzyme activity of FECH. In some embodiments, a subject with lead poisoning has increased levels of lead in the blood and / or urine. In some embodiments, a subject with lead poisoning has increased levels of ALA. In some embodiments, a subject with lead poisoning has increased levels of ALA and PBG. In some embodiments, a subject with lead poisoning has ALA levels that are increased by at least 10-fold over a reference value. In some embodiments, a subject with lead poisoning has ALA levels that are increased by at least 5-fold over a reference value. In some embodiments, the present disclosure relates to a method of treating lead poisoning in a subject, the method comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is further administered a chelating agent. In some embodiments, the chelating agent is 2,3-dimercaptosuccinic acid. In some embodiments, the chelating agent is calcium disodium ethylenediaminetetraacetate.

[0312] Porphyrins (e.g., 5-ALA, PBG, uroporphyrin, and coproporphyrin) can be found in various biological samples including skin, urine, feces, plasma, and erythrocytes. In some embodiments, the porphyrins may be extracted from a biological sample (e.g., plasma) into a solution for fluorescence analysis. Porphyrins can be detected in these biological samples by direct examination using long-wavelength ultraviolet light (e.g., light at 400 - 420 nm). Porphyrins have a maximum absorption wavelength near 400 - 420 nm, and their highest absorption peak occurs at 415 nm. The emission maximum of porphyrins is typically around 600 nm and varies slightly based on the type of porphyrin and the solvent used for analysis. In some embodiments, the diagnosis of hepatic porphyria may be performed using fluorescence analysis. In some embodiments, skin porphyrin levels can be measured by calculating the difference before and after complete photobleaching of skin porphyrins using controlled illumination. See, for example, Heerfordt IM. Br J Dermatol. 2016;175(6):1284-1289.

[0313] In some embodiments, the plasma porphyrin of interest fluoresces at a peak of 634 nm when irradiated with blue light (e.g., light in the range of 400 - 420 nm). In some embodiments, the plasma porphyrin of interest fluoresces at a peak in the range of 626 nm - 634 nm when irradiated with blue light (e.g., light in the range of 400 - 420 nm). In some embodiments, the skin porphyrin of interest fluoresces at a peak of 632 nm when irradiated with blue light (e.g., light in the range of 400 - 420 nm). In some embodiments, the skin porphyrin of interest fluoresces at a peak in the range of 626 nm - 634 nm when irradiated with blue light (e.g., light in the range of 400 - 420 nm). In some embodiments, a sample from a subject containing porphyrin or a porphyrin precursor (e.g., plasma or skin) fluoresces at a peak in the range of 615 nm - 620 nm when irradiated with blue light (e.g., light in the range of 400 - 420 nm). In some embodiments, a sample from a subject containing porphyrin or a porphyrin precursor (e.g., plasma or skin) fluoresces at a peak in the range of 624 nm - 627 nm when irradiated with blue light (e.g., light in the range of 400 - 420 nm). In some embodiments, the plasma of the subject is excited using a 405 nm laser. In some embodiments, the subject has red fluorescent urine.

[0314] Heme and heme intermediates Glycine is one of the important first substrates for heme and globin synthesis. Therefore, a decrease in glycine levels due to GlyT1 inhibition can lead to a decrease in heme synthesis. In certain embodiments, the present disclosure is a method of treating hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the heme level of the subject does not decrease by more than 10% (e.g., 10%, 15%, 20%, 25%, and 30%). In some embodiments, the present disclosure is a method of treating hepatic porphyria in a subject, wherein the heme level of the subject does not decrease by more than 15%. In some embodiments, the present disclosure is a method of treating hepatic porphyria in a subject, wherein the heme level of the subject does not decrease by more than 20%. In some embodiments, the present disclosure is a method of treating hepatic porphyria in a subject, wherein the heme level of the subject does not decrease by more than 25%. In some embodiments, the present disclosure is a method of treating hepatic porphyria in a subject, wherein the heme level of the subject does not decrease by more than 30%. In certain embodiments, the present disclosure is a method of treating hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, wherein the dosing of the pharmaceutical composition does not cause a substantial reduction in heme levels.

[0315] In some embodiments, the synthesis of one or more of the following heme intermediates (e.g., porphyrin precursors) is inhibited, and one or more heme intermediates are selected from the group consisting of 5-ALA, PBG, hydroxymethylbilane, ZPPIX, uroporphyrinogen I, uroporphyrinogen III, heptacarboxyporphyrinogen I, heptacarboxyporphyrinogen III, hexacarboxyporphyrinogen I, hexacarboxyporphyrinogen III, pentacarboxyporphyrinogen I, pentacarboxyporphyrinogen III, coproporphyrinogen I, coproporphyrinogen III, isocoproporphyrin, porphobilinogen; and protoporphyrinogen IX. In some embodiments, the present disclosure is a method of inhibiting 5-aminolevulinic acid (5-ALA) synthesis in a subject, comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the subject has hepatic porphyria. In some embodiments, the present disclosure is a method of inhibiting coproporphyrin III synthesis in vivo, comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure is a method of inhibiting zinc protoporphyrin IX (ZPPIX) synthesis in a subject, comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the subject has ALA dehydratase porphyria (ADP). In some embodiments, the present disclosure is a method of inhibiting porphobilinogen (PBG) synthesis in vivo, comprising administering to the subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof.In some embodiments, the present disclosure relates to a method of inhibiting 5-aminolevulinic acid (5-ALA) and porphobilinogen (PBG) synthesis in vivo, comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure relates to a method of inhibiting hydroxymethylbilane (HMB) synthesis in vivo, comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure relates to a method of inhibiting uroporphyrin III synthesis in vivo, comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure relates to a method of inhibiting heptacarboxyl-porphyrin synthesis in vivo, comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure relates to a method of inhibiting isocoproporphyrin synthesis in vivo, comprising administering to a subject a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof, or a prodrug of a GlyT1 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the synthesis of one or more heme intermediates (e.g., 5-ALA, coproporphyrin III, ZPPIX, PBG, HMB, uroporphyrin III, heptacarboxyl-porphyrin, and isocoproporphyrin) is inhibited in a dose-dependent manner.

[0316] In some embodiments, the accumulation of one or more of the following heme intermediates (e.g., porphyrin precursors) is inhibited, and the one or more heme intermediates are selected from the group consisting of 5-ALA, PBG, hydroxymethylbilane, ZPPIX, uroporphyrinogen I, uroporphyrinogen III, heptacarboxyporphyrinogen I, heptacarboxyporphyrinogen III, hexacarboxyporphyrinogen I, hexacarboxyporphyrinogen III, pentacarboxyporphyrinogen I, pentacarboxyporphyrinogen III, coproporphyrinogen I, coproporphyrinogen III, isocoproporphyrin, porphobilinogen; and protoporphyrinogen IX. In some embodiments, the accumulation of one or more heme intermediates (e.g., 5-ALA, coproporphyrin III, ZPPIX, PBG, HMB, uroporphyrin III, heptacarboxyl-porphyrin, and isocoproporphyrin) is inhibited in a dose-dependent manner.

[0317] In some embodiments, the subject to be treated according to the methods described herein has elevated levels of porphyrin or porphyrin precursors, such as ALA and / or PBG. In some embodiments, the subject has a porphyrin precursor level that is at least 10%, 20%, 30%, 40%, or 50% higher than the porphyrin precursor level in a healthy subject prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has an increased level of porphyrin precursor. In some embodiments, the porphyrin precursor is selected from the group consisting of 5-ALA, HMB, coproporphyrin III, ZPPIX, porphobilinogen, uroporphyrin III, heptacarboxyl-porphyrin, and isocoproporphyrin. In some embodiments, the subject has an increased level of uroporphyrin III (e.g., an increased level of uroporphyrin III in urine). In some embodiments, the subject has an increased level of 5-ALA (e.g., an increased level of 5-ALA in urine or plasma). In some embodiments, the subject has an increased level of HMB. In some embodiments, the subject has an increased level of coproporphyrin III (e.g., an increased level of coproporphyrin III in urine and feces). In some embodiments, the subject has an increased level of PBG (e.g., an increased level of PBG in urine). In some embodiments, the subject has an increased ratio of protoporphyrin to coproporphyrin in feces. In some embodiments, the subject has an increased level of heptacarboxyl-porphyrin (e.g., an increased level of heptacarboxyl-porphyrin in urine or feces). In some embodiments, the subject has an increased level of isocoproporphyrin (e.g., an increased level of isocoproporphyrin in feces). In some embodiments, the subject has an increased level of ZPPIX in red blood cells.

[0318] The levels of porphyrin or porphyrin precursors can be evaluated using methods known in the art or methods described herein. In some embodiments, the level of porphyrin or porphyrin precursor (e.g., ALA or PBG) in a subject is evaluated based on the absolute level of porphyrin or porphyrin precursor, e.g., ALA or PBG, in a sample from the subject. In some embodiments, the level of porphyrin or porphyrin precursor (e.g., ALA or PBG) in a subject is evaluated based on the relative level of porphyrin or porphyrin precursor (e.g., ALA or PBG) in a sample from the subject. In some embodiments, the relative level is relative to the level of another protein or compound in a sample from the subject, e.g., the level of creatinine. In some embodiments, the sample is a urine sample. In some embodiments, the sample is a plasma sample. In some embodiments, the sample is a fecal sample.

[0319] Elevated levels of porphyrin or porphyrin precursors (e.g., ALA and / or PBG) can be established by showing that the subject has a level of porphyrin or porphyrin precursor (e.g., plasma or urine levels of ALA and / or PBG) that is higher than, or higher than or equal to, a reference value. A physician with knowledge of the treatment of porphyria can determine, for example, for the purpose of diagnosing hepatic porphyria or whether a subject is at risk of developing hepatic porphyria, e.g., whether the subject is prone to acute attacks or conditions associated with porphyria, e.g., chronic pain (e.g., neuropathic pain) and neuropathy (e.g., progressive neuropathy), by determining whether the levels of porphyrin or porphyrin precursors (e.g., ALA and / or PBG) are elevated.

[0320] As used herein, "reference value" refers to a value from a subject when the subject is not in a diseased state, or a value from a normal or healthy subject, or a reference sample or population, e.g., a group of normal or healthy subjects (e.g., a group of subjects without mutations associated with hepatic porphyria and / or a group of subjects not suffering from symptoms associated with hepatic porphyria).

[0321] In some embodiments, the reference value is the pre-disease level in the same individual. In some embodiments, the reference value is the level in a reference sample or population. In some embodiments, the reference value is the mean or median level in a reference sample or population. In some embodiments, the reference value is a value that is greater than the mean in a reference sample or population by 2 standard deviations. In some embodiments, the reference value is a value that is greater than the mean in a reference sample or population by 2.5, 3, 3.5, 4, 4.5, or 5 standard deviations.

[0322] In some embodiments, the subject has a plasma or urine level of ALA or PBG that is higher than the reference value. In some embodiments where the subject has elevated levels of porphyrins or porphyrin precursors (e.g., ALA and / or PBG), the subject has a level of ALA and / or PBG that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% higher than the reference value. In some embodiments, the subject has a level of porphyrins or porphyrin precursors (e.g., ALA and / or PBG) that is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 times higher than the reference value.

[0323] In some embodiments, the reference value is the reference upper limit. As used herein, "reference upper limit" refers to the level that is the upper limit of the 95% confidence interval for a reference sample or population, e.g., a group of normal (e.g., wild-type) or healthy individuals, e.g., individuals without genetic mutations associated with porphyria and / or individuals not suffering from hepatic porphyria. Thus, the reference lower limit refers to the level that is the lower limit of the same 95% confidence interval.

[0324] In some embodiments, the subject has an elevated level (e.g., plasma level or urinary level) of porphyrin or porphyrin precursor that is higher than or equal to 2-fold, 3-fold, 4-fold, or 5-fold of a reference value (e.g., reference upper limit). In some embodiments, the subject has a urinary level of porphyrin or porphyrin precursor that is higher than 4-fold of the reference upper limit.

[0325] In some embodiments, the subject has a urinary level of PBG that is higher than or equal to 1.4 mmol / mol of creatinine. In some embodiments, the subject has a urinary level of PBG that is higher than or equal to 4.8 mmol / mol of creatinine. In certain embodiments, the subject has a urinary level of PBG that is higher than, or higher than or equal to, about 3, 4, 5, 6, 7, or 8 mmol / mol of creatinine.

[0326] In some embodiments, the reference value for plasma PBG is 0.12 μmol / L. In some embodiments, the subject has a plasma PBG level that is higher than, or higher than or equal to, 0.10 μmol / L, 0.12 μmol / L, 0.24 μmol / L, 0.36 μmol / L, 0.48 μmol / L, or 0.60 μmol / L. In some embodiments, the subject has a plasma level of PBG that is higher than, or higher than or equal to, 0.48 μmol / L.

[0327] In some embodiments, the reference value for urinary PBG is 1.2 mmol / mol of creatinine. In some embodiments, the reference value for urinary PBG is 1.4 mmol / mol of creatinine. In some embodiments, the subject has a urinary PBG level that is higher than, or higher than or equal to, 1.0 mmol / mol of creatinine, 1.2 mmol / mol of creatinine, 2.4 mmol / mol of creatinine, 3.6 mmol / mol of creatinine, 4.8 mmol / mol of creatinine, or 6.0 mmol / mol of creatinine. In some embodiments, the subject has a urinary PBG level that is higher than, or higher than or equal to, 4.8 mmol / mol of creatinine.

[0328] In some embodiments, the reference value for plasma ALA is 0.12 μmol / L. In some embodiments, the subject has a plasma ALA level that is higher than, or higher than or equal to, 0.10 μmol / L, 0.12 μmol / L, 0.24 μmol / L, 0.36 μmol / L, 0.48 μmol / L, or 0.60 μmol / L. In some embodiments, the subject has a plasma ALA level that is higher than, or higher than or equal to, 0.48 μmol / L.

[0329] In some embodiments, the reference value for urinary ALA is 3.1 mmol / mol of creatinine. In some embodiments, the reference value for urinary ALA is 6.3 mmol / mol of creatinine. In some embodiments, the subject has a urinary ALA level that is higher than, or higher than or equal to, 2.5 mmol / mol of creatinine, 3.1 mmol / mol of creatinine, 6.2 mmol / mol of creatinine, 6.3 mmol / mol of creatinine, 9.3 mmol / mol of creatinine, 12.4 mmol / mol of creatinine, or 15.5 mmol / mol of creatinine.

[0330] In some embodiments, the reference value for urinary uroporphyrin is lower than 4.5 μmol / mol of creatinine. In some embodiments, the subject has a urinary uroporphyrin level that is higher than, or higher than or equal to, 4.5 μmol / mol of creatinine, 9.0 μmol / mol of creatinine, 13.5 μmol / mol of creatinine, 18.0 μmol / mol of creatinine, 22.5 μmol / mol of creatinine, 27 μmol / mol of creatinine, or 31.5 μmol / mol of creatinine.

[0331] In some embodiments, the reference value for urinary coproporphyrin is lower than 20.7 μmol / mol of creatinine. In some embodiments, the subject has a urinary coproporphyrin level that is higher than, or higher than or equal to, 20.7 μmol / mol of creatinine, 41.4 μmol / mol of creatinine, 62.1 μmol / mol of creatinine, 82.8 μmol / mol of creatinine, 103.5 μmol / mol of creatinine, 124.2 μmol / mol of creatinine, or 144.9 μmol / mol of creatinine.

[0332] In some embodiments, the reference value for plasma porphyrin is 10 nmol / L. In some embodiments, the subject has a plasma porphyrin level that is higher than, or higher than or equal to, 10 nmol / L. In some embodiments, the subject has a plasma porphyrin level that is higher than, or higher than or equal to, 8, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nmol / L. In some embodiments, the subject has a plasma porphyrin level that is higher than, or higher than or equal to, 40 nmol / L.

[0333] In some embodiments, the reference value for urinary porphyrin is 25 μmol / mol of creatinine. In some embodiments, the reference value for urinary porphyrin is lower than 28.4 μmol / mol of creatinine. In some embodiments, the subject has a urinary porphyrin level that is higher than, or higher than or equal to, 25 μmol / mol of creatinine. In some embodiments, the subject has a urinary porphyrin level that is higher than or equal to 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 μmol / mol of creatinine.

[0334] In some embodiments, the subject has a level of porphyrin or porphyrin precursor (e.g., plasma level or urinary level) that is higher than 99% of individuals in samples from healthy individuals.

[0335] In some embodiments, the subject has a level of ALA or PBG (e.g., plasma level or urinary level) that is higher than the average level in samples from healthy individuals by more than 2 standard deviations.

[0336] In some embodiments, the subject has a urinary level of ALA that is 1.6 times or higher than the average level in normal subjects (e.g., subjects without mutations associated with porphyria). In some embodiments, the subject has a plasma level of ALA that is 2 or 3 times the average level in normal subjects. In some embodiments, the subject has a urinary level of PBG that is 4 times or higher than the average level in normal subjects. In some embodiments, the subject has a plasma level of PBG that is 4 times or higher than the average level in normal subjects.

[0337] In certain embodiments, administration of a GlyT1 inhibitor results in a decrease in the level of one or more porphyrins or porphyrin precursors (e.g., ALA and / or PBG) described herein. The decrease can be measured relative to any suitable control or reference value. For example, a decrease in the level of one or more porphyrins or porphyrin precursors can be established as at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or greater decrease compared to the level prior to treatment (e.g., immediately prior to treatment) in an individual subject. The decrease in the level of a porphyrin precursor, porphyrin, or porphyrin metabolite can be measured using any method known in the art.

[0338] In some embodiments, administration of a GlyT1 inhibitor is effective to reduce the level of ALA and / or PBG in a subject. The level of ALA or PBG in a subject can be evaluated, for example, based on the absolute level of ALA or PBG in a sample from the subject or based on the relative level of ALA or PBG (e.g., relative to the level of another protein or compound, e.g., creatinine). In some embodiments, the sample is a urine sample. In some embodiments, the sample is a plasma sample.

[0339] In some embodiments, the method reduces the 5-ALA level in a subject. In some embodiments, the method reduces the 5-ALA level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the HMB level in a subject. In some embodiments, the method reduces the HMB level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the coproporphyrin III level in a subject. In some embodiments, the method reduces the coproporphyrin III level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the PBG level in a subject. In some embodiments, the method reduces the PBG level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the uroporphyrin III level in a subject. In some embodiments, the method reduces the uroporphyrin III level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the ratio of protoporphyrin to coproporphyrin in a subject.In some embodiments, the method reduces the ratio of coproporphyrin to protoporphyrin in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the heptacarboxyl-porphyrin level in the subject. In some embodiments, the method reduces the heptacarboxyl-porphyrin level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the isocoproporphyrin level in the subject. In some embodiments, the method reduces the isocoproporphyrin level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the ZPPIX level in the subject. In some embodiments, the method reduces the ZPPIX level in the subject by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%). In some embodiments, the method reduces the porphyrin or porphyrin precursor (e.g., ALA or PBG) level in the subject to a normal level. In some embodiments, the normal level is a reference value for the porphyrin or porphyrin precursor described herein (e.g., urinary ALA level < 6.3 mmol / mol creatinine and urinary PBG level < 1.4 mmol / mol creatinine).

[0340] Complications of hepatic porphyria In certain embodiments, the present disclosure is a method of preventing, treating, or reducing the rate of progression and / or severity of one or more complications of hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, one or more complications of hepatic porphyria are acute photosensitivity, cutaneous photosensitivity, severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy, peripheral motor neuropathy, electrolyte abnormalities, nausea, vomiting, constipation, diarrhea, dysuria, ileus, paresthesia, insomnia, restlessness, agitation, anxiety, delirium, hallucinations, psychosis, seizures, pain associated with neuropathy, muscle paralysis, quadriplegia, respiratory depression, apnea, hyponatremia, tachycardia, hypertension, increased heart rate, increased blood pressure, red urine, dark urine, hepatocellular carcinoma, hypertensive kidney injury, chronic kidney disease, edema, erythema, anemia, hypochromic anemia, hemolytic anemia, hemolysis, mild hemolysis, severe hemolysis, chronic hemolysis, hypersplenism, palmar keratoderma, blisters, lesions, scarring, deformity, loss of fingernails, loss of fingers, cholestasis, cytolysis, gallstones, cholestatic liver failure, cholelithiasis, mild liver disease, worsening of liver disease, and end-stage liver disease. In some embodiments, one or more complications are improved indirectly. In some embodiments, the present disclosure contemplates a method of preventing one or more complications of hepatic porphyria, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof.In some embodiments, the present disclosure contemplates a method of reducing the rate of progression of one or more complications of hepatic porphyria, the method comprising administering to a subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof. In some embodiments, the present disclosure contemplates a method of reducing the severity of one or more complications of hepatic porphyria, the method comprising administering to a subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof.

[0341] The methods of treatment provided herein can serve to reverse one or more symptoms associated with hepatic porphyria or to reduce the risk of developing conditions associated with porphyria, such as neuropathy (e.g., progressive neuropathy), hepatocellular cancer. Symptoms associated with hepatic porphyria can include abdominal pain or cramps, headache, effects caused by nervous system abnormalities and photosensitivity, induction of rash, herpes, and skin scarring (actinic dermatitis). In certain embodiments, the hepatic porphyria is AIP. Symptoms of AIP can include gastrointestinal symptoms (e.g., severe and poorly localized abdominal pain, nausea / vomiting, constipation, diarrhea, ileus), urinary symptoms (urinary retention, urinary incontinence / retention, or dark urine), neurological symptoms (e.g., sensory neuropathy, motor neuropathy (e.g., affecting cranial nerves and / or leading to weakness in the arms or legs), seizure attacks, neuropathic pain, progressive neuropathy, headache, neuropsychiatric symptoms (e.g., confusion, anxiety, agitation, hallucinations, hysteria, delirium, emotional blunting, depression, phobia, psychosis, insomnia, somnolence, stupor), autonomic involvement (e.g., cardiovascular symptoms, e.g., tachycardia, hypertension, and / or arrhythmia, and other symptoms, e.g., increased circulating catecholamine levels, sweating, restlessness, and / or tremors), dehydration, and electrolyte abnormalities.

[0342] In some embodiments, the GlyT1 inhibitor is administered in combination with (e.g., before, after, or together with) another treatment that can serve to alleviate one or more of the above symptoms. For example, abdominal pain can be treated, e.g., with narcotic analgesics, seizure attacks can be treated, e.g., with antiepileptic drug therapy, nausea / vomiting can be treated, e.g., with phenothiazines, and tachycardia / hypertension can be treated, e.g., with beta blockers.

[0343] In certain hepatic porphyrias (e.g., VP, HCP, PCT, and HEP), porphyrin photosensitivity can result in two distinct clinical syndromes: (1) an acute photosensitivity to sunlight exposure with erythema and edema, and (2) a syndrome in which subepidermal blisters occur in areas of the skin exposed to sunlight. In certain embodiments, the present disclosure is a method of preventing, treating, or reducing the rate of progression and / or severity of hepatic porphyria in a subject, the method comprising administering to the subject a pharmaceutical composition comprising one or more glycine transporter inhibitors (e.g., GlyT1 inhibitors) or pharmaceutically acceptable salts thereof, or one or more prodrugs of glycine transporter inhibitors (e.g., GlyT1 inhibitors) or salts thereof, the method increasing painless light exposure in the subject. In some embodiments, the method increases painless light exposure in the subject by at least 10%, 20%, 30%, 40%, or 50% compared to painless light exposure prior to administration of the GlyT1 inhibitor. In some embodiments, the method reduces photosensitivity in the subject. In some embodiments, the method reduces photosensitivity in the subject by at least 10%, 20%, 30%, 40%, or 50% compared to photosensitivity prior to administration of the GlyT1 inhibitor. In some embodiments, the subject has a history of phototoxic reactions from hepatic porphyria. In some embodiments, the subject is an adult, child, infant, or pregnant female.

[0344] EC50 and Administration In certain embodiments of the methods and uses disclosed herein, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, or a prodrug of a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, demonstrates inhibition of a porphyrin precursor (e.g., 5-ALA or PBG) with an EC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, or less than 100 nM. In certain embodiments of the present application, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, or a prodrug of a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, demonstrates inhibition of a porphyrin precursor (e.g., 5-ALA or PBG) with an EC50 of less than 100 nM. In certain embodiments of the present application, a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, or a prodrug of a glycine transporter inhibitor, such as a GlyT1 inhibitor (e.g., a GlyT1 inhibitor disclosed herein) or a pharmaceutically acceptable salt thereof, demonstrates inhibition of a porphyrin precursor (e.g., 5-ALA or PBG) with an EC50 of less than 50 nM. In certain embodiments, the EC50 is measured in a flow cytometry assay. In certain embodiments, the EC50 is measured in an LC-MS / MS assay. In certain of the foregoing embodiments, the GlyT1 inhibitor is bitopertin or a pharmaceutically acceptable salt thereof, or a prodrug of bitopertin or a pharmaceutically acceptable salt thereof.

[0345] In certain embodiments, the GlyT1 inhibitor is administered to prevent recurrent seizures, such as periodic seizures associated with exacerbating factors, or to reduce their severity or frequency. In some embodiments, the exacerbating factor is the menstrual cycle. In some embodiments, the GlyT1 inhibitor is repeatedly administered, for example, at regular intervals, to prevent recurrent seizures, such as periodic seizures associated with exacerbating factors, such as the menstrual cycle, such as a particular stage of the menstrual cycle, such as the luteal phase, or to reduce their severity or frequency. In some embodiments, the GlyT1 inhibitor is administered during a particular stage of the menstrual cycle or based on the hormonal levels of the patient being treated (e.g., based on hormonal levels associated with a particular stage of the menstrual cycle). In some embodiments, the GlyT1 inhibitor is administered on one or more particular days of the menstrual cycle, such as days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 (or later days for subjects having longer menstrual cycles). In some embodiments, the GlyT1 inhibitor is administered on one or more days during the luteal phase, such as between days 14 - 28 of the menstrual cycle (or even later in subjects having menstrual cycles longer than 28 days). In some embodiments, ovulation in the subject is evaluated (e.g., using a blood or urine test to detect hormones associated with ovulation, such as LH), and the GlyT1 inhibitor is administered at a predetermined interval after ovulation. In some embodiments, the GlyT1 inhibitor is administered immediately after ovulation. In some embodiments, the GlyT1 inhibitor is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 days after ovulation. Any of these schedules can be repeated one or more times as needed. The number of repetitions can depend, for example, on reducing or preventing one or more symptoms associated with hepatic porphyria, reducing the frequency of seizures associated with hepatic porphyria, achieving the desired effect, such as a therapeutic or prophylactic effect.

[0346] In some embodiments, an initial dose of a GlyT1 inhibitor is administered and the levels of ALA or PBG are examined, for example, 1 to 48 hours after administration of the initial dose, such as 2, 4, 8, 12, or 24 hours later. In some embodiments, if the levels of ALA and / or PBG have decreased (e.g., until a predetermined reduction, such as normalization, is achieved) and / or if the symptoms associated with hepatic porphyria (e.g., pain) have improved (e.g., such that the patient is asymptomatic), no further dose is administered. However, if the levels of ALA and / or PBG have not decreased (e.g., a predetermined reduction has not been achieved, e.g., normalization has not occurred), a further dose of the GlyT1 inhibitor is administered. In some embodiments, the further dose is administered 12, 24, 36, 48, 60, or 72 hours after the initial dose. In some embodiments, if the initial dose is not effective in reducing the levels of ALA and / or PBG, the further dose is modified, e.g., increased, to achieve the desired reduction (e.g., a predetermined reduction, such as normalization) in the ALA or PBG level.

[0347] In some embodiments, the predetermined reduction is at least a 10%, 20%, 30%, 40%, or 50% reduction. In some embodiments, the predetermined reduction is a reduction effective to prevent or reverse symptoms, such as pain, prodromal symptoms, or recurrent attacks.

[0348] In some embodiments, the predetermined reduction is at least a 1, 2, 3, or higher standard deviation reduction, where the standard deviation is determined based on values from a reference sample, such as a reference sample described herein.

[0349] In some embodiments, the predetermined reduction is a reduction that brings the level of porphyrin or porphyrin precursor to a level below a reference value (e.g., a reference value described herein), or a level less than or equal to that value.

[0350] As used herein, “normalization” (or “normal” or “normalized” levels) of ALA or PBG levels refers to levels of either, or both, ALA or PBG (e.g., urinary and / or plasma levels) that are within the expected range for healthy individuals, asymptomatic individuals (e.g., individuals not experiencing pain and / or not suffering from neuropathy), or individuals without mutations associated with porphyria. For example, in some embodiments, normalized levels are within two standard deviations of the normal mean. In some embodiments, normalized levels are within the normal reference limits, e.g., within the 95% confidence interval, for appropriate control samples, e.g., samples from healthy individuals or individuals without genetic mutations associated with porphyria. In some embodiments, the subject's ALA and / or PBG levels (e.g., urinary and / or plasma ALA and / or PBG levels) are monitored periodically, and if the levels increase above the reference value, an additional dose of the GlyT1 inhibitor is administered.

[0351] Administration of the GlyT1 inhibitor can reduce porphyrin or porphyrin precursor levels in, for example, cells, tissues, blood, urine, or other patient compartments by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90%, or more. Administration of the GlyT1 inhibitor can also reduce porphyrin or porphyrin precursor levels during an acute attack of AIP.

[0352] Combination therapy Optionally, the methods disclosed herein for preventing, treating, or reducing the rate of progression and / or severity of one or more complications of hepatic porphyria in a subject may further comprise administering to the subject one or more supportive therapies or additional active agents for treating hepatic porphyria. For example, the subject may be administered avoidance of sunlight, topical sunscreen, skin protection, UVB phototherapy, afamelanotide (Scenesse®), bortezomib, heme infusion, adequate calorie support, givosiran, RNAi-mediated silencing of various enzymes (e.g., ALA synthase), avoidance of exacerbating factors, 4-aminoquinoline, chloroquine, hydroxychloroquine, phlebotomy, intravenous magnesium, LH-RH agonist, enzyme replacement therapy (e.g., recombinant human PBGD), gene therapy (e.g., transfer of the PBGD gene into liver cells by viral vectors), hemodialysis, pharmacological chaperone treatment, proteasome inhibitors, chemical chaperones, cholestyramine, activated charcoal, iron supplementation, liver transplantation, bone marrow transplantation, splenectomy, and transfusion, one or more supportive therapies or active agents selected from the group consisting of.

[0353] In some embodiments, the subject is administered a combination treatment, e.g., a GlyT1 inhibitor as described herein, and one or more additional treatments known to be effective against hepatic porphyria (e.g., glucose and / or heme products as described herein, e.g., hemin) or related symptoms thereof.

[0354] In one embodiment, the GlyT1 inhibitors described herein are administered in combination with glucose or dextrose. For example, 10-20% dextrose in saline may be provided intravenously. Typically, when glucose is administered, at least 300 g of 10% glucose is administered intravenously daily. The GlyT1 inhibitor may also be administered intravenously as part of the same infusion used to administer glucose or dextrose, or as a separate infusion administered before, together with, or after the administration of glucose or dextrose. In some embodiments, the GlyT1 inhibitor is administered by a different route of administration (e.g., subcutaneous). In yet another embodiment, the GlyT1 inhibitor is administered in combination with total parenteral nutrition. The GlyT1 inhibitor may be administered before, together with, or after the administration of total parenteral nutrition.

[0355] In certain embodiments, the GlyT1 inhibitor is administered in combination with one or more additional treatments, e.g., another treatment known to be effective in treating porphyria or symptoms of porphyria. In one embodiment, the GlyT1 inhibitor is administered in combination with a heme product (e.g., hemin, heme arginate, or heme albumin). In further embodiments, the GlyT1 inhibitor is administered in combination with a heme product and glucose, a heme product and dextrose, or a heme product and total parenteral nutrition. The additional treatment(s) may be administered before, after, or together with the administration of the GlyT1 inhibitor. The GlyT1 inhibitor and the additional therapeutic agent can be administered, for example, intravenously, in the same composition, or the additional therapeutic agent can be administered as part of a separate composition or by another method described herein. In some embodiments, the subject has been previously treated with a heme product (e.g., hemin, heme arginate, or heme albumin) described herein.

[0356] In some embodiments, administration of a GlyT1 inhibitor, or administration of a GlyT1 inhibitor in combination with one or more additional treatments (e.g., glucose, dextrose, etc.), reduces the frequency of acute seizures (e.g., by preventing acute seizures so that they no longer occur, or by reducing the number of seizures that occur over a particular period, e.g., fewer than a certain number of seizures occur per year). In some such embodiments, the GlyT1 inhibitor is administered according to a regular dosing regimen, e.g., b.i.d., daily, weekly, biweekly, or monthly.

Examples

[0357] Illustration The present invention will be more readily understood by reference to the following examples, which are given to illustrate the invention and are not intended to limit the invention, which has been generally described herein for the purpose of explaining certain specific embodiments of the invention.

[0358] (Example 1) Synthesis of Compounds

[0359] The compounds disclosed herein can be made by processes known and disclosed in the art according to well-known procedures. For example, compounds of formula I, such as bitopertin, can be prepared according to the synthetic protocols provided in U.S. Pat. Nos. 7,319,099, 9,877,963, and 7,812,161, the contents of which are incorporated herein by reference in their entirety. In addition, compounds of formula II, such as PF-3463275, can be prepared according to the synthetic protocol provided in U.S. Pat. No. 8,124,639, the content of which is incorporated herein by reference in its entirety.

[0360] (Example 2) Expression of GlyT1 in Hepatocytes

[0361] The liver is responsible for 15 - 20% of the heme synthesized in the human body. As a result, the enzymes of the heme synthesis pathway are generally highly expressed in the liver. Evaluation of GlyT1 expression in normal liver tends to show no GlyT1 expression. Thus, generally, it is thought that liver cells obtain glycine from endogenous metabolism and do not require the exogenous glycine source provided by GlyT1 expression. Nevertheless, the applicants evaluated the expression of GlyT1 in various cell lines and surprisingly found substantial GlyT1 expression in liver-derived cell lines. See Figure 1. The levels were higher than those observed in K562 of the erythroid cell line. Ibid. GlyT1 is known to be an important source of glycine that supports the induction of heme synthesis along with the maturation of erythroid cells. These data indicate that GlyT1 can be transiently expressed in liver cells as a support for increased heme synthesis requirements such as those characteristic of hepatic porphyria. Therefore, administration of a GlyT1 inhibitor has the potential to treat hepatic porphyria.

[0362] The cells were cultured under the conditions described in Table 2 below, and the GlyT1 mRNA levels were determined by standard methodologies.

Table 2

[0363] The applicants further evaluated the GlyT1 expression reported in the cancer cell database and determined that GlyT1 is expressed in many of the 26 liver cancer cell lines analyzed. See Figure 2. This data supports the initial conclusion that GlyT1 expression can be induced under certain conditions in normal liver cells. As a positive control, the applicants point out that other components of the heme synthesis pathway are expressed almost uniformly in liver cancer cell lines. Ibid. The second glycine transporter, GlyT2, is not expressed in liver cancer cell lines, indicating that GlyT2 is less likely to play a role in heme synthesis in the liver. Generally, GlyT2 is thought to be restricted to neural tissue.

[0364] (Example 3) Phenobarbital induces overexpression of ALAS1 and GlyT1 in HepG2 cells

[0365] Phenobarbital is used in the AIP mouse model to activate the heme synthesis pathway and induce AIP symptoms. It is known that phenobarbital stimulates the expression of ALAS1. The liver-derived cell line HepG2 was treated with phenobarbital for 24 and 48 hours. The expression of ALAS1 and GlyT1 was examined by qPCR. The mRNAs of ALAS1 (Figure 3A) and GlyT1 (Figure 3B) increased 3-fold and 6-fold, respectively, 24 and 48 hours after phenobarbital treatment. These results suggest that GlyT1 overexpression induced by phenobarbital treatment increases intracellular glycine levels and subsequent heme pathway intermediates, and thus may contribute to phenobarbital-induced AIP symptoms.

[0366] (Example 4) Effect of GlyT1 inhibitor on glycine uptake in hepatocyte cell lines

[0367] The liver-derived cell line HepG2 cells were engineered by lentiviral infection to overexpress untagged GlyT1 (Figure 4A) or HA-Flag-tagged GlyT1 (Figure 4B). Overexpression of GlyT1 was used to mimic the phenobarbital-induced AIP symptoms observed in HepG2 described in Example 3. The overexpression of the HA-Flag-tagged construct was confirmed by Western blot for GlyT1 protein. The overexpression of the untagged construct was confirmed by qPCR. Cells were cultured for 60 minutes at room temperature in the presence of the GlyT1 inhibitor vitropeltine, and then in the presence of 25 μM unlabeled glycine and 20 nM 3It was incubated for 60 minutes with H-labeled glycine. The uptake of glycine was measured by detection of the radioisotope level. In the presence of vitropeltin, glycine uptake in engineered HepG2 cells was significantly reduced with an IC50 in the range of 0.71 - 1.54 μM (Figure 4). This result suggests that GlyT1 inhibition reduces glycine uptake in hepatocytes, which can reduce intermediates in the heme synthesis pathway.

[0368] (Example 5) Effect of GlyT1 inhibitors on the accumulation of aminolaevulinic acid (5-ALA) and porphobilinogen (PBG) in the AIP cell model

[0369] HepG2, a cell line of liver origin, was engineered to express shRNA against HMBS, a gene in the heme biosynthesis pathway whose loss-of-function mutation causes hepatic porphyria. The shRNA reduced HMBS mRNA by 50% and HMBS protein by 70%. Hepatic porphyria is a latent disease activated by increased expression of ALAS1. To establish a cell model similar to the pathological state of hepatic porphyria, HepG2 cells with HMBS knockdown were also transduced with lentivirus to overexpress ALAS1 and GlyT1. By demonstrating an increase in the production of 5-ALA (Figure 5A) and PBG (Figure 5B), toxic heme pathway metabolites associated with the hepatic porphyria disease, it was confirmed that the genetically modified HepG2 cells model the pathological state of hepatic porphyria. Treatment of the modified HepG2 cells with vitropeltin, a GlyT1 inhibitor, was shown to significantly reduce the production of toxic metabolites.

[0370] The normal plasma glycine concentration in human adults ranges from 0.12 to 0.55 mM. To confirm that a GlyT1 inhibitor, such as bitopertin, can reduce the production of toxic metabolites under physiological conditions, modified HepG2 cells were treated with bitopertin in the presence of different concentrations of glycine (0.1 - 1 mM). Bitopertin treatment showed a consistent reduction in the toxic metabolites 5-ALA (Figure 6A) and PBG (Figure 6B), regardless of the glycine concentration in the medium.

[0371] Together, these data demonstrate that inhibiting glycine uptake suppresses the production of heme and its metabolic intermediates. Thus, a GlyT1 inhibitor, such as bitopertin, may have utility in controlling the production of toxic metabolites in patients with hepatic porphyria.

[0372] Incorporation by reference All publications and patents cited herein are hereby incorporated by reference in their entirety as if each individual publication or patent were specifically and individually indicated to be incorporated by reference.

[0373] Although specific embodiments of the subject matter have been discussed, the above specification is illustrative and not restrictive. Many modifications will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of the invention should be determined by reference to the claims, along with the full scope of their equivalents, and to this specification, along with such modifications.

Claims

1. A pharmaceutical composition for treating hepatic porphyria in a subject, wherein the pharmaceutical composition is 【Chemistry 127】 A pharmaceutical composition comprising a compound having the formula (vitopertine) or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the hepatic porphyria is acute hepatic porphyria.

3. The pharmaceutical composition according to claim 2, wherein the acute hepatic porphyria is acute intermittent porphyria (AIP).

4. The pharmaceutical composition according to claim 2, wherein the acute hepatic porphyria is ALA dehydratase porphyria (ADP).

5. The pharmaceutical composition according to claim 2, wherein the acute hepatic porphyria is atypical porphyria (VP).

6. The pharmaceutical composition according to claim 2, wherein the acute hepatic porphyria is hereditary coproporphyria (HCP).

7. The pharmaceutical composition according to claim 2, wherein the acute hepatic porphyria is harderoporphyria.

8. The pharmaceutical composition according to claim 1, wherein the hepatic porphyria is nonacute hepatic porphyria.

9. The pharmaceutical composition according to claim 8, wherein the nonacute hepatic porphyria is familial and sporadic porphyria (PCT) or myelohepatic porphyria (HEP).

10. The pharmaceutical composition according to claim 1, characterized in that the GlyT1 inhibitor exhibits an EC50 of less than 500 nM.

11. The pharmaceutical composition according to claim 1, characterized in that the GlyT1 inhibitor exhibits an EC50 of less than 100 nM.

12. The pharmaceutical composition according to claim 1, wherein the subject has or is at risk of developing hepatic porphyria and suffers from pain (e.g., neuropathic pain, e.g., chronic neuropathic pain) or neuropathy (e.g., progressive neuropathy).

13. The pharmaceutical composition according to claim 1, wherein the heme level of the subject is substantially maintained during treatment.

14. The pharmaceutical composition according to claim 1, wherein the treatment reduces the patient's heme level by more than 10% (for example, 10%, 15%, 20%, 25%, and 30%).

15. The pharmaceutical composition according to claim 1, wherein administration of the pharmaceutical composition does not cause a substantial reduction in heme levels.

16. The pharmaceutical composition according to claim 1, characterized in that the GlyT1 inhibitor is administered after an acute attack.

17. The pharmaceutical composition according to claim 1, characterized in that the GlyT1 inhibitor is administered during an acute attack.

18. The pharmaceutical composition according to claim 1, characterized in that the GlyT1 inhibitor is administered during the prodromal period.

19. The pharmaceutical composition according to claim 18, wherein the prodromal symptoms are characterized by pain (e.g., headache and / or abdominal pain), nausea, psychological symptoms (e.g., anxiety), restlessness and / or insomnia.

20. The pharmaceutical composition according to claim 1, characterized in that the GlyT1 inhibitor is administered prophylactically to prevent acute attacks of hepatic porphyria.

21. The pharmaceutical composition according to claim 1, characterized in that the GlyT1 inhibitor restores or prevents periodic attacks of hepatic porphyria.

22. The pharmaceutical composition according to claim 21, wherein the periodic seizures are related to an exacerbating factor.

23. The pharmaceutical composition according to claim 22, wherein the aggravating factor is selected from the group consisting of a specific stage of the menstrual cycle, the premenstrual phase, exposure to a chemical, exposure to lead, or drugs, xenobiotics, steroid hormones, smoking, alcohol, reduced calorie or carbohydrate intake, starvation, metabolic stress, and psychological stress.

24. The pharmaceutical composition according to claim 1, wherein administration of the pharmaceutical composition reduces pain or neuropathy.

25. The pharmaceutical composition according to claim 1, wherein administration of the pharmaceutical composition prevents acute attacks of hepatic porphyria.

26. The pharmaceutical composition according to claim 1, wherein administration of the pharmaceutical composition reduces or prevents nerve damage.

27. The pharmaceutical composition according to claim 1, characterized in that the GlyT1 inhibitor is administered prophylactically, starting in adolescence.

28. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

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