Methods and compositions for treating glucocorticoid excess

Abstract

The present disclosure provides a method of treating glucocorticoid excess in a patient in need thereof, the method comprising administering to the patient a pseudo-irreversible HSD-1 inhibitor.

Description

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 364,759, filed May 16, 2022, the disclosure of which is hereby incorporated by reference as if fully written herein.

[0002] Glucocorticoids (GCs) are corticosteroids that bind to glucocorticoid receptors (GRs), which are present on many cell types in the human body. GCs also bind to mineralocorticoid receptors (MRs) and nongenomic receptors. GCs are involved in cardiovascular, metabolic, immune, skeletal, muscular, skin, ocular, psychiatric, cognitive, circadian, and homeostatic functions. Excessive GCs in humans can lead to a wide range of symptoms and diseases.

[0003] GC can be endogenous (natural) or synthetic. Cortisol is an important endogenous glucocorticoid. Natural GC includes other active glucocorticoids (such as corticosterone) and is considered to be inactive glucocorticoids (such as cortisone) (because they do not activate GR or MR). Synthetic glucocorticoids include prednisone, prednisolone, methylprednisolone, dexamethasone, etc., and their derivatives. Cortisol (as a drug, commonly referred to as hydrocortisone) and synthetic GC are used as drugs for the treatment of autoimmune diseases and other conditions.

[0004] There are three main known forms of human GC excess. (1) Natural GC cortisol excess due to ACTH- or CRH-secreting tumors (including Cushing's disease (pituitary adenoma), ectopic ACTH secretion, and ectopic CRH secretion). (2) Cortisol excess due to cortisol-secreting tumors (including autonomous cortisol secretion [ACS; also known as mild autonomous cortisol secretion (MACS) or mild autonomous cortisol excess (MACE)] and adrenal Cushing's syndrome). (3) Hydrocortisone or synthetic GC excess during administration to treat autoimmune diseases or other conditions or to prevent transplant rejection.

[0005] HSD-1 is an intracellular enzyme that converts GC from an inactive (e.g., cortisone, prednisone) to an active (e.g., cortisol, prednisolone) form. It is the primary source of intracellular cortisol and is thought to be the primary source of intracellular GC synthesis in many cell types. Excessive intracellular GC activates GR and MR as well as non-genomic receptors, leading to tissue-specific morbidity observed in subjects with GC excess. Therefore, HSD-1 inhibition may improve these symptoms. This disclosure describes an important class of HSD-1 inhibitors—pseudo-irreversible HSD-1 inhibitors.

[0006] The present disclosure provides a method of treating glucocorticoid overdose in a patient in need thereof, the method comprising administering to the patient a pseudo-irreversible HSD-1 inhibitor.

[0007] The present disclosure also provides a method of ameliorating or preventing or reversing symptoms of glucocorticoid overdose in a patient in need thereof, the method comprising administering a pseudo-irreversible HSD-1 inhibitor to the patient.

[0008] The present disclosure also provides a method of reducing urine tetrahydrocortisol levels in a patient with glucocorticoid overdose, the method comprising administering a pseudo-irreversible HSD-1 inhibitor to the patient, wherein the urine tetrahydrocortisol levels are elevated compared to asymptomatic patients.

[0009] These and other aspects of the invention will become apparent upon reference to the following detailed description. To this end, various references are set forth herein that describe in more detail certain background information, procedures, compounds and / or compositions, and each of which is hereby incorporated by reference in its entirety. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 - Demonstrated inhibition of adipose HSD-1 by SPI-62. Adipose HSD-1 inhibition was detected 2-4 hours after a single dose, reached maximal measurable levels during the second dose interval, and was nearly identical between the second and 14 dose intervals.

[0011] Figure 2 - Demonstrates inhibition of hepatic HSD-1 by SPI-62 (formerly ASP3662). Data shown are the unitless ratio of tetrahydrocortisol to tetrahydrocortisone in urine, a standard measure of hepatic HSD-1 activity. The last daily SPI-62 dose was administered on Day 14. Follow-up was performed around Day 28.

[0012] Figure 3 - Shows inhibition of brain HSD-1 by SPI-62. Data shown are magnetic resonance (left) and positron emission tomography (center, right) images of the same individual before (left, center) and after (right) a single dose of SPI-62.

[0013] Figure 4 Urinary HSD-1 ratios are shown for the 3 mg, 6 mg, 10 mg, 30 mg, and 60 mg doses. Urinary HSD-1 ratios were measured in urine collected 0 to 6 (○), 6 to 12 (◇), 12 to 24 (+), 24 to 48 (●), and 48 to 72 (◆) hours after dosing. Plasma SPI-62 levels are from the midpoint of each collection; data at 9 and 60 hours post-dose were interpolated from surrounding data. Mean values ​​for six subjects in each group are shown.

[0014] Figure 5 - Demonstrating glucocorticoid (steroid) binding dependence of the HSD-1 tetramer conformation.

[0015] Figure 6 - Model showing the HSD-1 tetramer in the endoplasmic reticulum.

[0016] Figure 7 - Structure showing compound A bound to human HSD-1 (PDB record 2irw), showing an amide-like ternary complex with NADPH in the active site.

[0017] Figure 8 - Structure showing compound B bound to human HSD-1 (PDB record 3qqp), demonstrating an aromatic ternary complex with NADPH in the active site.

[0018] Figure 9 - Shown is the structure of BMS-823778 bound to human HSD-1 (PDB record 5qii), demonstrating a stacking-like ternary complex with NAPDH in the active site.

[0019] Figure 10 - Molecular docking model of SPI-62 and its interactions with pyrophosphate (left), serine (S) 170 / tyrosine (Y) 183 (center), and alanine (A) 172 backbone (center right), showing that it forms an amide-like ternary complex with NADPH in the HSD-1 active site.

[0020] Figure 11 - Shows the interaction of baseline parameter values ​​for treatment at Week 6 / End of Trial (EOT) for human subjects with painful diabetic peripheral neuropathy. Green circles and regression line are SPI-62; grey circles and regression line are placebo.

[0021] Figure 12 - Shown are representative mouse skin cross sections after 35 days of treatment with corticosterone (CORT) in the drinking water and oral SPI-62 or vehicle.

[0022] Figure 13 - Shown are food consumption and body weight statistics for mice that received corticosterone (CORT) in drinking water and gavage with SPI-62 or vehicle for 5 weeks. Food consumption was measured twice a week; weekly averages are shown. Body weight was measured daily; averages are shown.

[0023] Figure 14 - Demonstrated target-mediated drug disposition (TMDD) pharmacokinetic-pharmacodynamic (PK / PD) modeling of SPI-62, including inhibition of adipose HSD-1 as an effector. AS2570469 is the major metabolite of SPI-62, formed through conversion of the amide to the carboxylic acid. DETAILED DESCRIPTION Overview

[0024] The present disclosure provides a method for treating a patient with glucocorticoid (GC) overdose by administering a pseudo-irreversible inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) to the patient. The present disclosure also provides a method for improving or preventing specific symptoms in a patient with GC overdose by administering a pseudo-irreversible HSD-1 inhibitor. The present disclosure also provides a method for reducing urine tetrahydrocortisol levels in a patient with glucocorticoid overdose, the method comprising administering a pseudo-irreversible HSD-1 inhibitor to the patient, wherein the urine tetrahydrocortisol level is elevated compared to an asymptomatic patient. The present disclosure also provides a method for treating or improving specific symptoms in a patient with GC overdose by co-administering a pseudo-irreversible HSD-1 inhibitor with a GC drug.

[0025] In some embodiments, glucocorticoid excess refers to a condition or physiological state in an individual in which the level of urinary tetrahydrocortisol or other products of glucocorticoid breakdown is elevated relative to a reference patient or sample, or relative to a patient not experiencing glucocorticoid excess. In some embodiments, symptoms of glucocorticoid excess include cardiovascular, metabolic, immune, skeletal, muscular, skin, ocular, psychiatric, cognitive, circadian rhythm, and homeostatic symptoms.

[0026] In some embodiments, the pseudo-irreversible HSD-1 inhibitor does not exhibit tachyphylaxis to human adipose HSD-1 inhibition. In some embodiments, the HSD-1 inhibitor is selected from SPI-62 and BI-187004, or a pharmaceutically acceptable salt thereof. In some embodiments, the HSD-1 inhibitor is SPI-62 or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the pseudo-irreversible HSD-1 inhibitor is characterized by human pharmacokinetics consistent with target-mediated drug disposition. In some embodiments, the pseudo-irreversible HSD-1 inhibitor is selected from SPI-62, ABT-384, MK-0736, MK-0916, BMS-823778, UE-2343, AMG-221, and BI-187004, or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the plasma exposure of the pseudo-irreversible HSD-1 inhibitor is less than dose proportional after a single low dose, but is dose proportional after multiple low doses. In some embodiments, the dose is 10 mg or less, or 6 mg or less, or 4 mg or less.

[0029] In some embodiments, the pseudo-irreversible HSD-1 inhibitor is characterized by human pharmacodynamics consistent with target-mediated drug disposition. In some embodiments, the pharmacodynamic half-life of hepatic HSD-1 inhibition by the HSD-1 inhibitor is extended compared to its pharmacodynamic half-life. In some embodiments, the pseudo-irreversible HSD-1 inhibitor is characterized by a pharmacodynamic half-life of human hepatic HSD-1 inhibition of at least 1 week. In some embodiments, the pharmacodynamic half-life of human hepatic HSD-1 inhibition is at least 2 weeks. In some embodiments, the pharmacodynamic half-life of human hepatic HSD-1 inhibition is at least 4 weeks. In some embodiments, the pseudo-irreversible HSD-1 inhibitor is selected from SPI-62 and ABT-384, or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the pseudo-irreversible HSD-1 inhibitor is characterized by fast-on, slow-off in vitro binding kinetics to human HSD-1. In some embodiments, the HSD-1 inhibitor has a retention time of at least about 500 seconds. In some embodiments, the pseudo-irreversible HSD-1 inhibitor is selected from SPI-62, ABT-384, KR-67607, UE-2343, and BI-187004, or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the pseudo-irreversible HSD-1 inhibitors are characterized by significantly fast association and slow dissociation in vivo binding kinetics to human HSD-1. In some embodiments, the model-estimated k off Less than 0.3h -1 In some embodiments, the model estimates k off Less than 1.0h -1 In some embodiments, the model estimates k off Less than 3.0h -1 In some embodiments, the pseudo-irreversible HSD-1 inhibitor is selected from SPI-62 and ABT-384, or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the pseudo-irreversible HSD-1 inhibitor is characterized by having greater in vivo potency than in vitro potency. In some embodiments, the model-estimated K of the HSD-1 inhibitor is d Lower than the K of HSD-1 inhibitors i In some embodiments, the model estimates K d K i In some embodiments, the model estimated K d K i In some embodiments, the model estimated K d K iIn some embodiments, the model-estimated lipid IC of the HSD-1 inhibitor is at least 200-fold lower. 50 In some embodiments, the model estimated IC 50 At least 100-fold lower than in vitro measurements. In some embodiments, the model estimates the IC of fat 50 At least 300-fold lower than in vitro measurements. In some embodiments, the model estimates the IC of fat 50 At least 700-fold lower than in vitro measurements. In some embodiments, the pseudo-irreversible inhibitor is SPI-62 or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the pseudo-irreversible HSD-1 inhibitor forms a hydrogen bond with the pyrophosphate of NADPH at the active site of human HSD-1. In some embodiments, the pseudo-irreversible HSD-1 inhibitor is selected from SPI-62, ABT-384, KR-67607, SAR-184481, Compound A, and Compound B, or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the pseudo-irreversible HSD-1 inhibitor forms an aromatic stacking interaction with NADPH at the human HSD-1 active site. In some embodiments, the pseudo-irreversible HSD-1 inhibitor is selected from BMS-823778, MK-0916, Compound C, and Compound D, or a pharmaceutically acceptable salt thereof.

[0035] The present disclosure also provides a method for improving or preventing symptoms of glucocorticoid overdose in a patient in need thereof, the method comprising administering to the patient a brain penetrant pseudo-irreversible HSD-1 inhibitor. In one embodiment, the symptoms include mental (e.g., mood), cognitive or circadian (e.g., sleep) symptoms. In some embodiments, the mental symptoms are selected from depression, anxiety, hypomania, mania, and psychosis; or cognitive symptoms are selected from impairment of memory, visual spatial processing, reasoning, language learning, and language performance; or circadian rhythm symptoms are selected from insomnia, daytime fatigue, sleep apnea, sleep fragmentation, increased nocturnal motor activity, and REM sleep abnormalities.

[0036] In certain embodiments, the method described herein further includes administering a glucocorticoid drug to the patient. In certain embodiments, the HSD-1 inhibitor and the glucocorticoid drug are administered in fixed dose combination. In certain embodiments, the HSD-1 inhibitor and the glucocorticoid drug are co-packaged for separate administration. In certain embodiments, the HSD-1 inhibitor and the glucocorticoid drug are administered and packaged separately. In certain embodiments, the glucocorticoid drug is selected from prednisolone, methylprednisolone, dexamethasone, hydrocortisone, budesonide, deflazacort, beclomethasone, ciclesonide, fluticasone, mometasone, triamcinolone acetonide, flunisolone, clobetasol, betamethasone, fluocinolone acetonide, fluocinolone acetonide, clocortolone, halobetasol, desoximetasone, desonide, halcinonide, prednicarbate, diflorasone, amcinonide, alclomethasone, difluprednate, loteprednol, fluorometholone, rimexolone and medrysone, or its pharmaceutically acceptable salt or ester derivative.

[0037] In some embodiments, the patient has a tumor that secretes ACTH or CRH. In some embodiments, the patient has a tumor that secretes Cortisol.

[0038] In another embodiment, the pseudo-irreversible HSD-1 inhibitor is administered orally. In another embodiment, the pseudo-irreversible HSD-1 inhibitor is administered intravenously. In another embodiment, the pseudo-irreversible HSD-1 inhibitor is administered intramuscularly or subcutaneously. In another embodiment, the pseudo-irreversible HSD-1 inhibitor is administered by inhalation or intranasally. In another embodiment, the pseudo-irreversible HSD-1 inhibitor is administered ophthalmically. In another embodiment, the pseudo-irreversible HSD-1 inhibitor is administered topically.

[0039] The present disclosure describes an important class of HSD-1 inhibitors - pseudo-irreversible HSD-1 inhibitors, which have demonstrated previously unknown advantages for two members of this subclass, BI-187004 and SPI-62. Unlike certain other HSD-1 inhibitors (e.g., AZD4017, AZD8329, BI-135585), BI-187004 shows limited rapid tolerance to human adipose HSD-1 inhibition after multiple doses, while SPI-62 does not. Because adipose HSD-1 regulates the significant cardiometabolic morbidity of GC excess, inhibitors that do not lose adipose HSD-1 are expected to be clinically superior to other HSD-1 inhibitors in treating GC excess. It is believed that persistent human adipose HSD-1 inhibition is a common feature of pseudo-irreversible inhibitors, which are defined as HSD-1 inhibitors that display one or more of the following four properties.

[0040] (1) Clinical pharmacokinetics are consistent with target-mediated drug disposition (TMDD). After a single low dose, most of the administered dose is rapidly sequestered by the target, so only a small portion of the drug molecules is in the central circulation. Therefore, the drug plasma concentration is much lower than that of drugs with linear kinetics. As the single dose increases, the low-capacity target is rapidly saturated. The portion of the dose sequestered by the target decreases inversely with the dose. Therefore, the drug appears to have linear pharmacokinetics at high single doses because the portion captured by the target is minimal compared to the total dose. The significant nonlinear pharmacokinetics observed after one or more first low doses converts to linear pharmacokinetics after repeated low doses.

[0041] (2) Clinical pharmacodynamics are consistent with TMDD. Target engagement may be detected early after low doses, even before plasma levels are detected. Target engagement may appear to be concentration-independent over a wide dose range; high target engagement may be associated with low plasma levels. Pharmacological half-life can be greatly extended because the drug remains bound to the target in the microenvironment even when plasma levels drop below the limit of detection.

[0042] (3) Binds to HSD-1 rapidly and dissociates slowly, and the enzyme retention time (k d -1 ) is longer than that of other HSD-1 inhibitors. This results in a dissociation constant (k off ) is significantly lower than the association constant (k on ), which can be revealed by population PK modeling of clinical trial data. d (i.e. k off With k on The ratio of K i Due to the fast-on, slow-off binding, 50% maximal HSD-1 inhibition (IC 50 ) concentrations were much lower than the IC 50 , which can be revealed by population PK-PD modeling of clinical trial data.

[0043] (4) When bound to human HSD-1, it forms a non-covalent ternary complex with the enzyme and the cofactor NADPH. This is the structural basis for slow dissociation binding and TMDD behavior. The binding energy between the inhibitor and NADPH must be overcome for the inhibitor to dissociate from the enzyme. The ternary complex also resists competition from HSD-1 substrates, which is particularly important in GC excess when the circulating level of substrate increases. In some embodiments, hydrogen bonding and aromatic stacking interactions are different modes of attachment or complexation of HSD-1 inhibitors with NADPH at the active site. Cortisol and cortisone

[0044] Cortisol is a glucocorticoid produced and released by the adrenal glands. Less than 6% of circulating cortisol is bioavailable to tissues because it is extensively bound to corticosteroid-binding globulin and albumin. Circulating cortisone is much more bioavailable to tissues because its affinity for corticosteroid-binding globulin is only 12% of that of cortisol. Elevated glucocorticoid levels can lead to insulin resistance by reducing insulin-dependent glucose uptake, enhancing hepatic gluconeogenesis, and inhibiting insulin secretion from pancreatic cells. Patients with persistent glucocorticoid excess may develop dyslipidemia, visceral obesity, and other metabolic syndromes. Other physical symptoms may include rapid weight gain (primarily in the face, chest, and abdomen, contrasting with slender arms and legs), flushing and rounding of the face, hypertension, osteoporosis, dermatological changes (such as bruising and purple stretch marks), muscle weakness, and mood swings (manifested as anxiety, depression, or irritability).

[0045] Cortisone levels have been observed to increase with administration of pseudo-irreversible HSD-1 inhibitors. For example, single and multiple doses of SPI-62 significantly increased hepatic cortisone levels, as evidenced by increases in urinary excretion of the cortisone metabolite, tetrahydrocortisone. In healthy adults given a single dose of 10, 20, or 50 mg SPI-62 (n=40), the least squares mean (standard error) of tetrahydrocortisone was 32.71 (1.149) μmol, compared to 9.19 (2.300) μmol after a single dose of matched placebo (n=10). In the same subjects, after 14 daily doses, SPI-62 produced 42.73 (1.968) μmol of tetrahydrocortisone, compared to 8.51 (0.410) μmol for placebo. Similar results have been observed in elderly individuals. Previous studies have also shown that the administration of ABT-384 to healthy adults and elderly subjects for 7-21 days significantly increased liver cortisone levels, as evidenced by an increase in urinary tetrahydrocortisone. In patients with painful diabetic peripheral neuropathy who took 10 mg of SPI-62 for 6 consecutive weeks, circulating cortisone levels increased significantly, while serum Cortisol did not change. For example, on the last day of study drug administration, the serum cortisone of SPI-62 was 56.0 (2.37) nM (n=36), while the placebo was 38.8 (2.16) nM (n=36). In addition, after two weeks, the serum cortisone of SPI-62 was 49.5 (1.75) nM, while the placebo was 38.7 (1.70) nM. Similar cortisone results were not obtained in healthy adults. Urine tetrahydrocortisol

[0046] In some embodiments, a pseudo-irreversible HSD-1 inhibitor can be administered to a patient to reduce the patient's urinary tetrahydrocortisol level. The main excretion route of cortisol is as urinary metabolites. The total amount of these metabolites best represents the total glandular output of cortisol on that day. Cortisol is mainly excreted as 5-α-tetrahydrocortisol (5α-THF) and 5-β-tetrahydrocortisol (5β-THF) and tetrahydrocortisone (THE). Urinary metabolites with lower levels include cortisol pentahydrocortisol and cortisol tetrahydrocortisol. A small portion (1%-3%) is excreted as cortisol and cortisone, and cortisone itself is a metabolite of cortisol. Measurement of urinary cortisol and urinary tetrahydrocortisol within 24 hours can be used to indicate the patient's daily cortisol production level. The present disclosure also provides a method for reducing a patient's urinary tetrahydrocortisol level, the method comprising administering a pseudo-irreversible HSD-1 inhibitor to a patient, wherein the level of urinary tetrahydrocortisol is elevated compared to asymptomatic patients. Structures of pseudo-irreversible HSD-1 inhibitor compounds

[0047] A variety of pseudo-irreversible HSD-1 inhibitors are known and available in the art, including but not limited to SPI-62, ABT-384, MK-0736, MK-0916, BMS-823778, UE-2343, AMG-221, KR-67607, BI-187004, SAR-184481, Compound A, Compound B, Compound C, Compound D, BMS-823778, or pharmaceutically acceptable salts thereof. As will be appreciated by those skilled in the art, any pseudo-irreversible HSD-1 inhibitor described herein or known or available in the art can be used as described herein and is encompassed within the scope of the present disclosure.

[0048] The structures of some of the pseudo-irreversible HSD-1 inhibitors described herein are shown below. All structures and IUPAC names were generated using ChemDraw 20.0.

[0049] As used herein, "SPI-62" refers to 4-(5-(2-(4-chloro-2,6-difluorophenoxy)propan-2-yl)-4-methyl-4H-1,2,4-triazol-3-yl)-3-fluorobenzamide.

[0050] As used herein, "BMS-823778" refers to 2-(3-(1-(4-chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propan-2-ol.

[0051] As used herein, "ABT-384" refers to (1s,3R,4r,5S,7s)-4-(2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propionamido)adamantane-1-carboxamide.

[0052] As used herein, "UE-2343" refers to (5-(1H-pyrazol-4-yl)thiophen-3-yl)((1R,3r,5S)-3-hydroxy-3-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-8-yl)methanone.

[0053] As used herein, "MK-0736" refers to 3-(4-(3-(ethylsulfonyl)propyl)bicyclo[2.2.2]octan-1-yl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-4H-1,2,4-triazole.

[0054] As used herein, "AMG-221" refers to (S,E)-2-(((1S,2S,4R)-bicyclo[2.2.1]hept-2-yl)imino)-5-isopropyl-5-methylthiazolidin-4-one.

[0055] As used herein, "MK-0916" refers to 3-((1s,3s)-1-(4-chlorophenyl)-3-fluorocyclobutyl)-4,5-dicyclopropyl-4H-1,2,4-triazole.

[0056] As used herein, "KR-67607" refers to (1s,3R,4s,5S,7s)-4-(2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazin-2-yl)acetamido)adamantane-1-carboxamide.

[0057] As used herein, "BI-187004" refers to (4aR,9aS)-1-(1H-benzo[d]imidazole-6-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carbonitrile.

[0058] As used herein, "AZD4017" refers to (S)-2-(1-(5-(cyclohexylcarbamoyl)-6-(propylthio)pyridin-2-yl)piperidin-3-yl)acetic acid.

[0059] As used herein, "AZD8329" refers to 4-(4-(((1r,3r,5r,7r)-adamantan-2-yl)carbamoyl)-5-(tert-butyl)-1H-pyrazol-1-yl)benzoic acid.

[0060] As used herein, "BI-135585" refers to (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one.

[0061] As used herein, "SAR-184841" refers to 4-(5-(4-(tert-butyl)piperazin-1-yl)pyridin-2-yl)-N-((1R,3S,5s,7s)-5-carbamoyladamantan-2-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide.

[0062] As used herein, "Compound A" refers to (1s,3R,5S,7s)-4-(2-(4-methoxyphenoxy)-2-methylpropionamido)adamantane-1-carboxamide.

[0063] As used herein, "Compound B" refers to 3,4-dihydroquinolin-1(2H)-yl[4-(1H-imidazol-5-yl)piperidin-1-yl]methanone.

[0064] As used herein, "Compound C" refers to (5R)-2-[(2-fluorophenyl)amino]-5-(1-methylethyl)-1,3-thiazol-4(5H)-one.

[0065] As used herein, "Compound D" refers to 3-(2-fluoroethyl)-4-((4-[(2S)-1,1,1-trifluoro-2-hydroxypropan-2-yl]phenyl)sulfonyl)benzonitrile. Symptoms of glucocorticoid overdose

[0066] The present disclosure also provides a method for treating or ameliorating specific symptoms in patients with GC excess by administering a pseudo-irreversible HSD-1 inhibitor. Symptoms of GC excess may vary from individual to individual, but common symptom domains may include, but are not limited to, cardiovascular, metabolic, immune, skeletal, muscular, skin, ocular, psychiatric, cognitive, circadian rhythm, and homeostatic symptoms. In some embodiments, brain-penetrant pseudo-irreversible HSD-1 inhibitors may be used to treat symptoms related to mood, cognition, and sleep.

[0067] In some embodiments, specific symptoms associated with excess cortisol may include, but are not limited to, weight gain and deposition of fat tissue (particularly around the abdomen and upper back, between the face and shoulders), pink or purple stretch marks (stripe) on the skin of the abdomen, thighs, breasts, and arms, thin, fragile skin, easy bruising, fatigue, frequent illness, slow healing of bruises and wounds, fragile bones, muscle weakness, high blood sugar, anxiety and depression, sleep problems, and difficulty concentrating. In some embodiments, chronically high cortisol levels can lead to heart disease, osteoporosis, diabetes, and poor mental health.

[0068] In some embodiments, cardiovascular symptoms associated with GC excess may include, but are not limited to, hypertension (including lack of nocturnal blood pressure dip), atherosclerosis, endothelial dysfunction, prothrombotic states, coronary artery disease, heart failure, and stroke.

[0069] In some embodiments, metabolic symptoms associated with GC excess may include, but are not limited to, obesity, glucose intolerance, insulin resistance, diabetes, and dyslipidemia (including hypercholesterolemia and hypertriglyceridemia).

[0070] In some embodiments, immune symptoms associated with GC excess may include, but are not limited to, infections (including opportunistic infections) and sepsis.

[0071] In some embodiments, bone symptoms associated with GC excess may include, but are not limited to, osteoporosis, osteonecrosis, osteopenia, hypocalcemia (through decreased absorption or increased renal elimination or effects on vitamin D and PTH), impaired linear bone growth (stature), and fractures (including low-impact or compression fractures).

[0072] In some embodiments, muscle symptoms associated with GC excess may include, but are not limited to, muscle atrophy and muscle weakness.

[0073] In some embodiments, dermatological symptoms associated with GC excess may include, but are not limited to, impaired wound healing, thin or fragile skin, abnormal accumulation of subcutaneous fat, plethora of skin, purple striae, acanthosis nigricans, hyperpigmentation, and easy bruising.

[0074] In some embodiments, ocular symptoms associated with GC excess may include, but are not limited to, increased intraocular pressure, glaucoma, proptosis, and cataracts.

[0075] In some embodiments, psychiatric symptoms associated with GC excess may include, but are not limited to, depression, anxiety, hypomania, mania, and psychosis.

[0076] In some embodiments, cognitive symptoms associated with GC excess may include, but are not limited to, impairments in memory, visuospatial processing, reasoning, verbal learning, and language performance.

[0077] In some embodiments, circadian rhythm symptoms associated with GC excess may include, but are not limited to, insomnia, daytime fatigue, sleep apnea, sleep fragmentation, increased nocturnal motor activity, and abnormal REM sleep.

[0078] In some embodiments, steady-state symptoms associated with GC excess may include, but are not limited to, hypokalemia, hypernatremia, hypophosphatemia, hypercalciuria, growth hormone suppression, and thyroid disease (including hypothyroidism and hyperthyroidism). Lack of fat tachyphylaxis

[0079] The present disclosure also provides a method for treating or ameliorating glucocorticoid overdose or its symptoms in a patient by administering a pseudo-irreversible HSD-1 inhibitor that does not exhibit tachyphylaxis to HSD-1 inhibition in human adipose tissue. Competition for elevated levels of HSD-1 substrates (inactive GC) can lead to adipose tachyphylaxis. GC (both active and inactive forms) is highly lipophilic and, therefore, is expected to accumulate in tissues of patients, particularly those with GC overdose, and particularly in adipose tissue, following administration of an HSD-1 inhibitor, as described herein.

[0080] In some embodiments, the pseudo-irreversible HSD-1 inhibitors useful in the present disclosure may be any pseudo-irreversible HSD-1 inhibitor known or available in the art. Some exemplary pseudo-irreversible HSD-1 inhibitors include, but are not limited to, SPI-62, ABT-384, MK-0736, MK-0916, BMS-823778, UE-2343, AMG-221, KR-67607, BI-187004, SAR-184481, Compound A, Compound B, Compound C, Compound D, or pharmaceutically acceptable salts thereof. One skilled in the art will recognize that other pseudo-irreversible HSD-1 inhibitors may be used without departing from the scope of the present disclosure. In some embodiments, the pseudo-irreversible HSD-1 inhibitor is selected from SPI-62, ABT-384, KR-67607, SAR-184481, Compound A, and Compound B, or pharmaceutically acceptable salts thereof. In some embodiments, the pseudo-irreversible HSD-1 inhibitor is selected from BMS-823778, MK-0916, Compound C, and Compound D, or a pharmaceutically acceptable salt thereof. In some embodiments, the pseudo-irreversible HSD-1 inhibitor is selected from SPI-62, ABT-384, MK-0736, MK-0916, BMS-823778, UE-2343, and AMG-221, or a pharmaceutically acceptable salt thereof. In some embodiments, the pseudo-irreversible HSD-1 inhibitor is selected from SPI-62, ABT-384, KR-67607, UE-2343, and BI-187004, or a pharmaceutically acceptable salt thereof. In some embodiments, the pseudo-irreversible HSD-1 inhibitor is selected from SPI-62 and ABT-384, or a pharmaceutically acceptable salt thereof. In some embodiments, the pseudo-irreversible HSD-1 inhibitor is SPI-62 or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the pseudo-irreversible HSD-1 inhibitors described herein are administered to a patient or subject with elevated levels of glucocorticoids or urinary tetrahydrocortisol to reduce the level of glucocorticoids or urinary tetrahydrocortisol in the patient or subject. In some embodiments, once the patient's symptoms are alleviated or eliminated, administration of the pseudo-irreversible HSD-1 inhibitor can be suspended or stopped, and administration can be restarted if necessary if the clinician or physician deems it appropriate. In some embodiments, the present disclosure provides chronic treatment of chronic GC excess conditions in patients by administering a pseudo-irreversible HSD-1 inhibitor without pausing or stopping the medication. In some embodiments, pseudo-irreversible inhibitors provide the advantage that they maintain efficacy during brief periods of drug withdrawal (e.g., a patient neglects to take medication for several days or even weeks).

[0082] In some embodiments, the dosage of the pseudo-irreversible HSD-1 inhibitors described herein can be any dosage deemed appropriate by a healthcare practitioner or clinician. In some embodiments, the pseudo-irreversible inhibitor is administered at a molar dose sufficient to occupy all HSD-1 in the body. In some embodiments, the pseudo-irreversible HSD-1 inhibitor achieves and maintains full target engagement at low doses. In some embodiments, the pseudo-irreversible HSD-1 inhibitor achieves and maintains full target engagement at submilligram doses.

[0083] In some embodiments, the pseudo-irreversible HSD-1 inhibitor is administered in a single dose of about 1 to about 40 mg (including 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, etc.). In some embodiments, a submilligram dose can be any dose approximately equal to or less than 1 mg, such as 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, or 1 mg. In some embodiments, a single dose of a pseudo-irreversible HSD-1 inhibitor, as described herein, may be suitable for patients with chronic GC overdose. In some embodiments, a single dose of a pseudo-irreversible inhibitor is administered intravenously.

[0084] In some embodiments, the pseudo-irreversible HSD-1 inhibitor may be administered in multiple doses over a specified period of time. Multiple doses may refer to multiple doses per day, or alternatively, may refer to a single dose per day over a period of time deemed appropriate by the clinician or healthcare professional.

[0085] In some embodiments, the dose of SPI-62 ranges from about 0.2 mg to about 6 mg once daily. In some embodiments, the dose of SPI-62, ABT-384, MK-0736, or MK-0916 is about 10 mg or less. In some embodiments, the dose of UE-2343 is about 10 mg to about 35 mg. In some embodiments, the dose of BI-187004 is about 20 mg to about 240 mg.

[0086] In some embodiments, the administration period of the pseudo-irreversible HSD-1 inhibitor can be any period of time, for example, including but not limited to 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, etc. The time period according to the present disclosure can be any period of time, for example, 1-14 days, or 7-14 days, or 7-10 days or 10-14 days. In other embodiments, the administration period of the HSD-1 inhibitor can be 7-30 days, or 7-21 days, etc. In some embodiments, the administration period of the pseudo-irreversible HSD-1 inhibitor can be 1 day, 6 days or 12 days. In some embodiments, the pseudo-irreversible HSD-1 inhibitor can be continuously administered to the patient to control chronic GC excess. In some embodiments, the dose of the pseudo-irreversible HSD-1 inhibitor can be administered for 1 month, or 2 months, or 3 months, or 4 months, or 5 months, or 6 months, or 7 months, or 8 months, or 9 months, or 10 months, or 11 months, or 12 months, or 15 months, or 18 months, or 24 months, or 36 months, or 48 months or longer. In some embodiments, the pseudo-irreversible HSD-1 inhibitor can be administered intravenously as a single high dose, for example, to control sepsis or prevent the development of side effects of steroid use (e.g., in diabetic patients).

[0087] As described herein, pseudo-irreversible HSD-1 inhibitors (1) should not exhibit lipid tachyphylaxis, (2) should exhibit TMDDPK and PD, (3) should exhibit fast association and slow dissociation kinetics, and (4) should be linked to NADPH in the active site. However, only one of these features is required to indicate that a molecule is a pseudo-irreversible HSD-1 inhibitor.

[0088] In some embodiments, the pseudo-irreversible HSD-1 inhibitors described herein (eg, SPI-62, ABT-384, etc.) are characterized by human pharmacokinetics consistent with target-mediated drug disposition as described herein.

[0089] In some embodiments, the pseudo-irreversible HSD-1 inhibitor has a long pharmacodynamic half-life for human hepatic HSD-1 inhibition. In some embodiments, the pharmacodynamic half-life of the HSD-1 inhibitor for hepatic HSD-1 inhibition is prolonged compared to its own pharmacokinetic half-life. In some embodiments, the half-life of human hepatic HSD-1 inhibition is at least 1 week, or 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks, or 6 weeks, etc.

[0090] In some embodiments, pseudo-irreversible HSD-1 inhibitors exhibit fast association, slow dissociation binding kinetics with human HSD-1. In some embodiments, retention time is an indicator of the fast association, slow dissociation binding kinetics of an HSD-1 inhibitor. Pseudo-irreversible HSD-1 inhibitors can be identified by in vitro enzyme kinetic assessment, where they are expected to exhibit longer enzyme retention times compared to other HSD-1 inhibitors. In some embodiments, the HSD-1 inhibitors described herein exhibit a retention time of at least about 500 seconds. As will be appreciated by those skilled in the art, the retention time threshold can vary with different buffers, NADPH concentrations, or enzyme concentrations.

[0091] In some embodiments, an initial dose of a pseudo-irreversible HSD-1 inhibitor initially binds and remains bound to its target in a tissue. In some embodiments, up to about 3 mg of the pseudo-irreversible HSD-1 inhibitor is sequestered from central circulation. In some embodiments, the pseudo-irreversible HSD-1 inhibitor exhibits nonlinear pharmacokinetics after a single dose in the submilligram to low milligram range and has dose-proportional exposure after multiple doses. In some embodiments, plasma exposure of the HSD-1 inhibitor is less than dose-proportional after a single low dose and is dose-proportional after multiple low doses. In some embodiments, the dose is 10 mg or less, for example, 10 mg, or 9 mg, or 8 mg, or 7 mg, or 6 mg, or 5 mg, or 4 mg, or 3 mg, or 2 mg, or 1 mg, or less than 1 mg. In some embodiments, the dose is 6 mg or less, or 4 mg or less.

[0092] In some embodiments, the pharmacokinetic profile of a pseudo-irreversible HSD-1 inhibitor (e.g., SPI-62) is a two-compartment TMDD population pharmacokinetic model with three transport-absorption compartments and an estimated target capacity of approximately 2.5 mg to 3.6 mg. In some embodiments, the K of the pseudo-irreversible HSD-1 inhibitor is d Lower than K i In some embodiments, the pseudo-irreversible HSD-1 inhibitor has a K of d K i In some embodiments, the pseudo-irreversible HSD-1 inhibitor has a K d K i In some embodiments, the in vivo IC of the pseudo-irreversible HSD-1 inhibitor against hepatic HSD-1 is at least 60-fold lower. 50 In some embodiments, the in vivo IC of the pseudo-irreversible HSD-1 inhibitor against hepatic HSD-1 is at least 50-fold lower than the in vitro measured value. 50 In some embodiments, the estimated in vivo fat IC of the pseudo-irreversible HSD-1 inhibitor for HSD-1 is about 200-fold lower than the in vitro measured value. 50In some embodiments, the in vivo fat IC of the pseudo-irreversible HSD-1 inhibitor is lower than the in vitro measured value of the HSD-1 inhibitor. 50 In some embodiments, the in vivo fat IC of the pseudo-irreversible HSD-1 inhibitor is at least 100-fold lower than the in vitro measured value. 50 This is approximately 700 times lower than the value measured in vitro.

[0093] In some embodiments, a pseudo-irreversible HSD-1 inhibitor can be co-administered with a glucocorticoid. In some embodiments, a pseudo-irreversible HSD-1 inhibitor and a glucocorticoid are co-administered in a fixed-dose combination, co-packaged, or prescribed separately. As described herein, the glucocorticoid can be a glucocorticoid known or available in the art, including, but not limited to, prednisolone, methylprednisolone, dexamethasone, hydrocortisone, budesonide, deflazacort, beclomethasone, ciclesonide, fluticasone, mometasone, triamcinolone acetonide, flunisolone, clobetasol, betamethasone, fluocinolone acetonide, fluocinolone acetonide, clocortolone, halobetasol, desoximetasone, desonide, halcinonide, prednicarbate, diflorasone, amcinonide, alclomethasone, difluprednate, loteprednol, fluorometholone, rimexolone, and medrysone. Ester prodrugs of glucocorticoids used to prolong the duration of pharmacological action (e.g., prednisolone acetate and prednisolone hemisuccinate) or pharmaceutically acceptable salts thereof are also suitable for and included within the scope of this disclosure. In certain embodiments, specific glucocorticoid drugs may be modified when a medical practitioner or clinician deems it appropriate. In certain embodiments, the glucocorticoid drug may not be prednisone or cortisone, which are inactive prodrugs that require HSD-1 to activate.

[0094] In some embodiments, the pseudo-irreversible HSD-1 inhibitors described herein can be administered by any route deemed appropriate by a healthcare practitioner or clinician. Suitable routes of administration include, but are not limited to, oral, intravenous, intramuscular, subcutaneous, inhalation, intranasal, ocular, and topical. definition

[0095] The definitions and methods provided define the disclosure and guide those of ordinary skill in the art in the practice of the disclosure. Unless otherwise indicated, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art.

[0096] As used herein, "brain penetrant" refers to a drug or compound that crosses the blood-brain barrier. In some embodiments, brain penetrant pseudo-irreversible HSD-1 inhibitors are used to treat symptoms of glucocorticoid excess related to mood, cognition, and sleep.

[0097] As used herein, "glucocorticoid excess" refers to a condition or physiological state in an individual in which the level of an active glucocorticoid (e.g., Cortisol or a synthetic glucocorticoid) is elevated relative to a reference patient or sample, or relative to a patient not experiencing glucocorticoid excess.

[0098] As used herein, "pseudo-irreversible HSD-1 inhibitor" refers to a compound, such as a small molecule compound, that binds to, interacts with, induces a conformational change, or otherwise inhibits or abrogates the activity of HSD-1.

[0099] As used herein, "pseudo-irreversible inhibition" refers to hydrogen bonding or aromatic stacking interactions with the HSD-1 cofactor NADPH and the inhibitor molecule. Through these, a ternary complex is formed that is more resistant to dissociation (i.e., binds more strongly, not weakly) than other HSD-1 inhibitors that form only binary complexes with the enzyme.

[0100] As used herein, "tachyphylaxis" refers to a weakening of the response to successive doses of a drug, making the drug less effective. Tachyphylaxis refers to the onset of drug insensitivity.

[0101] As used herein, an “effective amount” of a compound refers to an amount sufficient to produce a desired response (e.g., to reduce or eliminate the signs or symptoms of a condition or disease). For example, as described herein, an effective amount may be the amount of a pseudo-irreversible HSD-1 inhibitor required to treat a patient's glucocorticoid overdose. An effective amount of a pseudo-irreversible HSD-1 inhibitor may be the amount necessary to improve or prevent a patient's glucocorticoid overdose symptoms or reduce the patient's urine tetrahydrocortisol level. Generally speaking, this amount is sufficient to measurably alleviate the symptoms of glucocorticoid overdose or reduce the patient's urine tetrahydrocortisol level. When administered to a subject, a dose that reaches a target tissue concentration (e.g., in the liver, adipose tissue, brain, bone, muscle, skin, eyes) is typically used, which has been shown to achieve an acceptable level of glucocorticoid or urine tetrahydrocortisol, i.e., a level that does not cause the patient to experience glucocorticoid overdose symptoms. In some instances, an “effective amount” is an amount that treats one or more symptoms. In one instance, an effective amount is a therapeutically effective amount. In one instance, an effective amount is an amount that prevents or reverses one or more signs or symptoms of glucocorticoid overdose.

[0102] As used herein, " reduction (reducing or reduced) " refers to the reduction or reduction of the amount or level of, for example, one or more glucocorticoids or urine tetrahydrocortisol in the patient's body relative to a reference sample or a patient. As used herein, reduction refers to the level of glucocorticoids or urine tetrahydrocortisol being reduced to the level where no physiological symptoms are found or no physiological symptoms occur in the patient's body.

[0103] As used herein, a "reference sample" or "reference patient" is a sample or patient to whom a pseudo-irreversible HSD-1 inhibitor has not been administered as described herein, or a healthy patient.

[0104] As used herein, "subject" or "patient" refers to a human. A patient or subject according to the present disclosure suffers from a glucocorticoid overdose. Unless otherwise indicated, the terms "patient" or "subject" are used interchangeably herein. In some embodiments, the patient or subject described herein suffers from a tumor that secretes ACTH or CRH. In some embodiments, the patient or subject suffers from a tumor that secretes cortisol.

[0105] As used herein, "tetrahydrocortisol" refers to urinary tetrahydrocortisol or cortisol, the levels of which are altered by administration of an HSD-1 inhibitor.

[0106] The terms "treating" or "alleviating" include administering a compound or agent to a patient to alleviate or reverse the symptoms of a disease, condition, or disorder, or to arrest or inhibit its further development. Subjects in need of treatment include those already suffering from a disease or disorder or experiencing symptoms of a disease, condition, or disorder, for example, a patient with elevated glucocorticoid or urinary tetrahydrocortisol levels.

[0107] The numbers representing the amount of components, properties such as molecular weight, reaction conditions, etc. used to describe and claim certain embodiments of the present disclosure should be understood to be modified by the term "about" in some cases. In some embodiments, the term "about" is used to indicate that a value includes a measure of the variability of the device or method used to determine the value. The numerical parameters set forth in the written description and the appended claims are approximate values, which can vary depending on the desired properties sought to be obtained in a particular embodiment. The numerical parameters should be interpreted based on the number of reported significant figures and by applying ordinary rounding techniques. Although the numerical ranges and parameters setting forth the wide range of some embodiments of the present disclosure are approximate values, the numerical values ​​set forth in the specific embodiments are reported as accurately as possible. The numerical values ​​presented in some embodiments of the present disclosure may contain certain errors that are inevitably caused by the variability found in their corresponding test measurements. The description of the value range herein is intended only to be used as a shorthand method for individually referring to each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually described herein.

[0108] The terms "a" and "an" and "the" and similar referents used in the context of describing particular embodiments (especially in the context of some of the following claims) may be construed to cover both the singular and the plural, unless specifically stated otherwise. The term "or" as used herein (including the claims) is used inclusively unless explicitly stated to refer only to alternatives or the alternatives are mutually exclusive.

[0109] The terms "comprises," "having," and "includes" are open-ended linking verbs. Any form or tense of one or more of these verbs (such as "comprises," "comprising," "has," "having," "includes," and "including") are also open-ended. For example, any method that "comprises," "has," or "includes" one or more steps is not limited to having only those one or more steps, and may also cover other unlisted steps. Similarly, any composition or device that "comprises," "has," or "includes" one or more features is not limited to having only those one or more features, and may cover other unlisted features.

[0110] All methods described herein can be performed in any suitable order, unless otherwise specified herein or otherwise clearly contradictory to the context. The use of any and all examples or exemplary language (e.g., "such as") provided with respect to certain embodiments herein is intended only to better illustrate this disclosure and does not limit the scope of this disclosure, unless otherwise stated. Any language in this specification should not be construed as indicating that any unclaimed element is necessary for practicing this disclosure.

[0111] The grouping of alternative elements or embodiments of the present disclosure disclosed herein should not be construed as limiting. Each group member may be mentioned and claimed individually or in any combination with other members of the group or other elements found herein. For reasons of convenience or patentability, one or more members of a group may be included in or deleted from the group.

[0112] Having described the present disclosure in detail, it is clear that modifications, variations and equivalent embodiments are possible without departing from the scope of the present disclosure as defined in the appended claims. Furthermore, it should be understood that all examples in the present disclosure are provided as non-limiting examples. Examples

[0113] Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented only by way of illustration and to assist one of ordinary skill in the art in using the present disclosure. These examples are not intended to further limit the scope of the present disclosure in any way. Example 1. Inhibition of adipose HSD-1 by SPI-62.

[0114] The contradictory observations reported for the three HSD-1 inhibitors suggest tachyphylaxis of adipose HSD-1 inhibition in humans and may be considered a class effect. The following HSD-1 inhibitors showed greater adipose HSD-1 inhibition after a single dose compared with after multiple doses, even though plasma drug levels increased to steady state after repeated dosing, and hepatic HSD-1 inhibition was observed after both single and multiple doses.

[0115] In subjects with abdominal obesity, AZD4017 demonstrated adipose HSD-1 inhibition after a single dose, but no sustained inhibition after repeated dosing. AZD4017 also demonstrated no skin HSD-1 inhibition after multiple doses, although it correlated with maximal liver HSD-1 inhibition in the same subjects. As there are no data following a single dose, it is unclear whether AZD4017 demonstrates tachyphylaxis of skin HSD-1 inhibition or if other explanations may be possible. Clinical benefits (improved wound healing) were observed in the skin of subjects receiving AZD4017 compared to subjects receiving placebo. The ex vivo assay used to measure skin HSD-1 activity may not be specific.

[0116] In human adipose tissue, inhibition of HSD-1 activity was lost following repeated administration of AZD8329 compared to acute administration.

[0117] Median HSD-1 enzyme inhibition in human adipose tissue reached 90% after a single dose of BI-135585, but was lower (31% or less) after 14 days of continuous treatment.

[0118] Pseudo-irreversible HSD-1 inhibitors are not predicted to exhibit tachyphylaxis in human adipose HSD-1 inhibition. This is based on the hypothesis that adipose tachyphylaxis results from competition for increased levels of HSD-1 substrates (inactive GCs). Inactive GCs are highly lipophilic and therefore expected to accumulate in tissues of patients treated with HSD-1 inhibitors, particularly those with GC excess, and particularly in adipose tissue.

[0119] BI-187004, which we identified as a pseudo-irreversible HSD-1 inhibitor based on its fast-binding, slow-dissociating in vitro enzyme kinetics, exhibits limited tachyphylaxis to human adipose HSD-1 inhibition. For example, the median HSD-1 enzyme inhibition in human adipose tissue associated with the 20 mg dose was 92.4% on day 2 and 78.1% on day 15. For the 240 mg dose, the median values ​​were 99.5% on day 2 and 93.1% on day 15. The discrepancy between days 2 and 15 may be due to the fact that, for logistical reasons, adipose samples were obtained 10 to 45 minutes after the day 2 dose and 24 hours after the day 14 dose on day 15.

[0120] Cortisone is an endogenous HSD-1 substrate with a K m is 1.9 mM and has a logP of 1.25. Prednisone is a common GC drug and a prodrug that requires HSD-1 for activation to prednisolone. It is also the major metabolite of prednisolone, another common GC drug. Its K for human HSD-1 is m The pH value is 20.6 mM and the logP is 1.5.

[0121] For competitive inhibitors (such as AZD4017, AZD8329, or BI-135585), increased tissue levels of cortisone, prednisone, or other lipophilic HSD-1 substrates are problematic. When a substrate (such as cortisone or prednisone) accumulates in tissues, it can compete with the inhibitor because HSD-1 does not convert it to its active form. This is consistent with the observation that these three compounds significantly inhibit adipose HSD-1 after a single dose, but inhibition is less pronounced after multiple doses. This phenomenon may be more prevalent in adipose (and possibly skin) compared to liver due to lower tissue blood flow, higher lipid content, and possibly other factors. In contrast, pseudo-irreversible inhibitors are less sensitive to competition with substrate accumulation and are better able to maintain HSD-1 inhibition and its attendant clinical benefit. This prediction was confirmed in clinical trials.

[0122] SPI-62 was administered daily for 14 days to male and non-menstrual female subjects with type 2 diabetes aged 18 to 65 years and a body mass index between 30.0 and 45.0. Perfusate T1 (MDialysis, Stockholm, Sweden) plus 1 μg / mL D8 cortisone ([2,2,4,6,6,9,12,12-]) in 0.5% ethanol USP was administered via a microdialysis catheter (63 microdialysis catheter, M Dialysis, Stockholm, Sweden) at a rate of 1 μL / min for at least 4 hours before and during the 1st, 2nd, and 14th dosing intervals. 2 [H8] cortisone (Millipore Sigma, Miamisburg, OH) was continuously infused into subcutaneous abdominal adipose tissue. Adipose dialysate was collected at two-hour intervals (0-2, 2-4, 4-6, 6-8, 8-10, 20-22, and 22-24 hours after the SPI-62 dose) and analyzed for D8 cortisone and D8 cortisol. The D8 cortisol mole percentage fraction (MPF) was calculated as: ([2, 2, 4, 6, 6, 9, 12, 12- 2 H8]Cortisol*368.51) / ([2,2,4,6,6,9,12,12- 2H8] cortisone * 370.52), where 368.51 and 370.52 are the molar masses of D8 cortisone and D8 cortisol respectively. The percentage of adipose HSD-1 inhibition was calculated as: 100*(1-(MPF t / MPF 基线 ).

[0123] The time of sample (t) was considered the midpoint of the collection interval. Assay sensitivity limits quantification of adipose HSD-1 inhibition to approximately 90%-95%, depending on the D8 cortisone value, since D8 cortisol values ​​below the lower limit of quantification were estimated as the lower limit of quantification. Data shown represent the median inhibition observed in two subjects receiving a daily dose of 6 mg SPI-62.

[0124] like Figure 1 As shown, adipose HSD-1 inhibition was detected 2-4 hours after a single dose, reached maximal measurable levels during the second dose interval, and was nearly identical during dose intervals 2 and 14. In other subjects who received SPI-62 doses of 1 mg, 2 mg, 3 mg, or 10 mg, maximal measurable adipose HSD-1 inhibition was observed after multiple doses, even though no or limited adipose HSD-1 inhibition was associated with lower single SPI-62 doses. Example 2. Pseudo-irreversible HSD-1 inhibitors identified by human pharmacokinetics

[0125] Pseudo-irreversible HSD-1 inhibitors can be identified based on human pharmacokinetic data. Because an initial dose of a pseudo-irreversible HSD-1 inhibitor initially binds and remains bound to its target in tissues, it can sequester up to approximately 3 mg from the central circulation. Consequently, after a single dose in the submilligram to low-milligram range, pharmacokinetics exhibit significant and consistent nonlinearity, with dose-proportional exposure after multiple doses. Based on human pharmacokinetic data, the following are identified as pseudo-irreversible HSD-1 inhibitors.

[0126] Substantially nonlinear plasma exposure was observed following single dose administration of SPI-62 (formerly ASP3662); single doses of 0.7 mg to 3 mg were associated with dose-normalized plasma levels that were much lower than those observed with higher single doses. Plasma levels were approximately dose-proportional after 14 days of dosing for SPI-62 doses ranging from 0.2 mg to 50 mg (a 3 mg loading dose was administered before daily 0.2 mg doses). The single- and multiple-dose pharmacokinetics of SPI-62 were well characterized using a two-compartment TMDD population pharmacokinetic model with three transport-absorption compartments and an estimated target volume of approximately 2.5 mg of SPI-62, consistent with a dose range where pharmacokinetic nonlinearity was prominent.

[0127] Substantially nonlinear plasma exposure was observed following single ABT-384 dose administration; single doses of 1 mg to 4 mg were associated with dose-normalized plasma levels that were much lower than those of higher single doses. Plasma levels were roughly dose-proportional after 14 days of dosing for ABT-384 doses ranging from 1 to 100 mg. The single- and multiple-dose pharmacokinetics of ABT-384 were well characterized using a two-compartment TMDD population pharmacokinetic model with three transport-absorption compartments and an estimated target capacity of approximately 1 mg SPI-62 (this is consistent with the dose range where pharmacokinetic nonlinearity is prominent and is likely an underestimate, as no data from submilligram doses are available). ABT-384 was reported to be retained in the liver of cynomolgus monkeys for at least 77 days.

[0128] SPI-62 and ABT-384 have K d K i A remarkable and unexpected property of about 60 times lower.

[0129] MK-0736 exhibits nonlinear, saturable distribution PK, resulting in a shortened half-life with increasing dose and dose-dependent accumulation. The population pharmacokinetics of MK-0736 is described by a two-compartment model with first-order absorption, linear elimination, and saturable distribution. The administered dose range is 1.2 mg to 200 mg, so a saturable distribution may be observed at doses similar to SPI-62 and ABT-384, which is consistent with those precedents for the HSD-1 inhibitor TMDD. The authors of the study (clinical pharmacology experts at Merck) were apparently unaware of TMDD and therefore used a less appropriate model structure to model MK-0736 pharmacokinetics.

[0130] Substantially nonlinear plasma exposure was observed following single MK-0916 dose administration; single doses of 0.2 mg to 3.16 mg were associated with dose-normalized plasma levels that were much lower than those observed with higher single doses. For MK-0916 doses of 0.2 mg to 50 mg, plasma levels were roughly dose-proportional after 14 or 28 days of dosing. The pharmacokinetic data were fit to a two-compartment saturation distribution model. The dose range over which pharmacokinetic linearity was observed was similar to that for SPI-62, suggesting that MK-0916 is also subject to HSD-1-mediated TMDD. The study authors (clinical pharmacology experts at Merck) were apparently unaware of TMDD and therefore used a less appropriate model structure to model MK-0916 pharmacokinetics. The estimated saturation distribution capacity of approximately 3 mg of MK-0916 is consistent with the dose range over which pharmacokinetic nonlinearity is prominent and the target capacity of SPI-62 estimated using the TMDD model.

[0131] BMS-823778 plasma levels were undetectable after a single 0.1 mg or 0.5 mg dose, and less than dose-proportional plasma levels were achieved after a single 2 mg dose. Steady-state exposure was dose-proportional from 0.5 mg daily. These observations are consistent with the clinical pharmacokinetic behavior of the HSD-1 inhibitors TMDD, which are best characterized by SPI-62 and ABT-384. Physiologically based pharmacokinetic models overestimated exposure after the first dose at low levels. The study authors (clinical pharmacology experts at BMS) attributed the shortcomings of their model to unknown mechanisms, and therefore, apparently, ignorance of HSD-1-mediated TMDD.

[0132] Following single doses of 2 mg and 5 mg, UE2343 plasma levels were below the level of quantification. Following single doses of 10 mg to 35 mg, exposure increased in a greater than dose-proportional manner. The graph shows that the mean maximum plasma concentration measured after a single 10 mg dose (40.4 ng / mL) was well above the assay quantification value (by visual inference, no more than approximately 5 ng / mL). Multiple-dose data for doses < 10 mg were not reported. A population pharmacokinetic model has not been reported. TMDD due to pseudo-irreversible HSD-1 inhibition by UE2343 is the most likely explanation for the data.

[0133] AMG-221 exhibits nonlinear pharmacokinetics, with lower dose-normalized exposure after a single 3 mg dose compared with a single 30 mg or 100 mg dose. Plasma level data were characterized by a two-compartment open model with linear elimination from the central compartment, which slightly overestimated exposure associated with the higher doses. AMG-221 appears to exhibit human pharmacokinetics consistent with TMDD, although data are unavailable following repeated dosing, and based solely on pharmacokinetic evidence, inferences are less clear than for other HSD-1 inhibitors.

[0134] Dose-normalized plasma levels of BI-187004 were significantly lower after a single 2.5 mg dose, and levels after a single 5 mg dose were lower than those associated with single doses of 10 mg and higher. Multiple-dose data below 10 mg were not reported. A population pharmacokinetic model has not been reported. TMDD resulting from pseudo-irreversible HSD-1 inhibition by BI-187004 is the most likely explanation for the data. Example 3. Pseudo-irreversible HSD-1 inhibitors identified by human pharmacodynamics

[0135] Pseudo-irreversible HSD-1 inhibitors can be identified using human pharmacodynamic data. Since the inhibitors dissociate slowly from the enzyme, the following are characteristics of pseudo-irreversible HSD-1 inhibitors.

[0136] HSD-1 inhibition will be observed long after drug cessation, particularly in the liver where HSD-1 protein concentration is highest, which could further promote long-term interactions. Due to the high HSD-1 concentration in the ER, an inhibitor molecule that dissociates from one enzyme molecule is theoretically more likely to bind to another before being distributed from the ER.

[0137] Target inhibition can be associated with very low plasma levels. Although circulating pseudo-irreversible HSD-1 inhibitor molecules are not bound to the enzyme and can therefore be eliminated by similar pathways and at similar rates to other HSD-1 inhibitors, the prolonged binding to the intracellular enzyme provides a compartment from which the pseudo-irreversible HSD-1 inhibitor can only very slowly re-enter the circulation. Even with highly sensitive assays, HSD-1 inhibition can be associated with plasma drug levels near or below the limit of quantification and well below the molecule's K for human HSD-1. i or IC 50 The level of unbound (i.e., tissue accessible) is correlated with the level of

[0138] Following a single dose, a delayed and concentration-independent pattern of HSD-1 inhibition will be observed. When a pseudo-irreversible HSD-1 inhibitor is absorbed from the gastrointestinal tract, it is first distributed to the liver, which contains the highest concentration of HSD-1 to which the drug can bind and remain bound without entering the central circulation. At low doses, substantial HSD-1 inhibition may be observed before the drug reaches plasma levels above the limit of quantification. Following a single dose of a pseudo-irreversible HSD-1 inhibitor, hepatic HSD-1 inhibition may not vary significantly as drug plasma levels increase and then decrease, particularly if the dose is sufficient to saturate hepatic HSD-1 (up to approximately 3 mg of drug capacity in healthy adults).

[0139] In hepatocytes, 5- and 3-steroid reductases sequentially metabolize cortisol (a product of HSD-1) into tetrahydrocortisol and allotetrahydrocortisol, and cortisone (a substrate of HSD-1) into tetrahydrocortisone. The tetrahydro metabolites are rapidly and extensively excreted in the urine. Therefore, the urine (tetrahydrocortisol + allotetrahydrocortisol) / tetrahydrocortisone ratio is a biomarker of liver enzyme activity. Continuous adrenal synthesis provides a circulating pool of cortisol, of which the free portion (approximately 5%) enters cells. This prevents the urine HSD-1 ratio from falling below approximately 0.1. Therefore, values ​​within this range are considered to indicate maximal inhibition of hepatic HSD-1.

[0140] Hepatic HSD-1 inhibition, as assessed by the urine HSD-1 ratio, was persistent after cessation of SPI-62 administration. In healthy adults, the urine HSD-1 ratio did not fully return to baseline more than 2 weeks after the last dose. For example, the mean urine HSD-1 ratio was 55% lower than baseline 16 ± 2 days after discontinuation of the daily dose of SPI-62 0.7 mg, and 84% lower than baseline on the last dosing day. Figure 2 Similar data were observed after 10 mg of SPI-62 was administered daily for 6 weeks to patients with painful diabetic peripheral nephropathy. The mean urine HSD-1 ratio was 1.06 before dosing, 0.13 on the last dosing day, and 0.33 2 weeks after the last dose.

[0141] By interacting with HSD-1-specific PET ligand [ 11 C] In a competition evaluation of AS2471907, a single dose of SPI-62 3 mg resulted in brain HSD-1 occupancy of 84%-90% at 3.3 to 25 hours, 56%-83% at 42 to 46 hours, 36%-45% at 139 hours, and 26% at 189 hours. As expected, the pharmacological half-life of SPI-62 in the brain is shorter than in the liver. Figure 3 .

[0142] The lowest SPI-62 dose administered clinically to date was 0.2 mg daily for 14 days, which was associated with a mean reduction of 87% from baseline in the urine HSD-1 ratio on the last day of dosing, at which time the mean maximum plasma drug concentration (C max ) was <1 ng / mL. This corresponds to an unbound concentration of <0.25 nM, which is much lower than the K of SPI-62 for human HSD-1. i 5.3nM and IC 50 17 nM. Within the SPI-62 dose range of 0.2 mg to 50 mg, the mean urine HSD-1 ratios for each dose group ranged from 0.09 to 0.17. The final urine HSD-1 ratios were independent of concentration; the corresponding C max The mean range was <1 to 835 ng / mL. A single dose of SPI-6 21 mg resulted in a mean difference of 51% in the urine HSD-1 ratio compared to placebo, and a mean C max <0.05 ng / mL (unbound concentration <0.012 nM). After a single dose of 6 mg to 60 mg SPI-62, the mean urine HSD-1 ratio was between 0.11 and 0.18; the corresponding C max Mean values ​​ranged from 28 ng / mL to 595 ng / mL.

[0143] The expected hysteresis pattern was observed after administration of a single dose of SPI-62. Urine HSD-1 ratios were determined in urine collected 0 to 6 (○), 6 to 12 (◇), 12 to 24 (+), 24 to 48 (●), and 48 to 72 (◆) hours after dosing (see Figure 4 Plasma SPI-62 levels are from the midpoint of each collection; data at 9 and 60 hours post-dose were interpolated from surrounding data. Mean values ​​for 6 subjects in each group are shown.

[0144] No unchanged concentration-response relationship was observed for partial hepatic HSD-1 within the first 6 hours post-dose. This may be due to inter-group variability during the initial distribution phase, during which there was little or no HSD-1 inhibition. For intervals after the initial distribution phase, similar mean urine HSD-1 ratios between 0.1 and 0.2 correlated with plasma drug levels of <2 to >300 ng / mL and the time interval from 6 to 72 hours post-dose. No hysteresis plot was shown for the single 1 mg dose of SPI-62, as drug levels were below the LLOQ (0.1 ng / mL). In urine collected from 0 to 6, 6 to 12, 12 to 24, 24 to 48, and 48 to 72 hours post-dose, the mean urine HSD-1 ratios following the 1 mg dose were 0.694, 0.471, 0.472, 0.522, and 0.618, respectively, indicating partial hepatic HSD-1 inhibition.

[0145] ABT-384 was also reported to exhibit prolonged HSD-1 inhibition in vivo. Similar hepatic HSD-1 inhibition was measured in healthy adults following seven daily doses of ABT-384 1 to 100 mg, with corresponding mean C max In a Phase 1 clinical trial, complete brain HSD-1 inhibition was observed up to 40 hours after cessation of daily ABT-384 administration in healthy adults.

[0146] Following a single oral dose of 3 mg of AMG-221, the expected hysteresis pattern was observed. These data increase confidence that AMG-221 is a pseudo-irreversible HSD-1 inhibitor. Example 4. Pseudo-irreversible HSD-1 inhibitors identified by in vitro enzyme kinetics

[0147] Pseudo-irreversible HSD-1 inhibitors can be identified through in vitro enzyme kinetic assessments, where they are expected to exhibit longer enzyme retention times compared to other HSD-1 inhibitors. Surface plasmon resonance (SPR) is the resonant oscillation of conduction electrons at the interface between a negative dielectric constant material and a positive dielectric constant material stimulated by incident light. When proteins are bound to a surface, SPR can be used to detect ligand binding to proteins.

[0148] Previously, it was reported that ABT-384 rapidly forms a tight enzyme-inhibitor complex with the HSD-1 enzyme in vitro, but the dissociation rate is very slow.

[0149] The binding affinity and kinetics of 19 HSD-1 inhibitors were characterized using SPR. Each compound was tested using the ABA method in 50 mM Tris, 150 mM NaCl, 2% DMSO, pH 7.4, using a parallel experimental design at a flow rate of 30 μL / min. The enzyme was exposed to 300 μM NADPH in 50 mM Tris, 150 mM NaCl, 2% DMSO, pH 7.4 for 90 seconds (A step), followed by exposure to a buffer solution containing 300 μM NADPH and the test compound for 150 seconds (B step), followed by exposure to a buffer solution containing 300 μM NADPH for 300 to 370 seconds (A step). Association and dissociation of the test compound were monitored in the presence of 300 μM NADPH throughout the experiment. Four concentrations of test compounds were prepared by two-fold serial dilution in 50 mM Tris, 150 mM NaCl, 2% DMSO, pH 7.4 containing 300 μM NADPH. The retention time (reciprocal of the dissociation rate constant) for each compound is shown in Table 1 below. Table 1. Retention time of HSD-1 inhibitors

[0150] Based on these results, ABT-384, BI-187004, UE-2343, SPI-62, and KR-67607 were identified as possible pseudo-irreversible HSD-1 inhibitors.

[0151] The reason for classifying only these is as follows.

[0152] Although clinical pharmacokinetic or pharmacodynamic data for KR-67607 have not yet been published, its enzyme retention time is very similar to that of SPI-62, which has also been identified as a pseudo-irreversible HSD-1 inhibitor based on clinical pharmacokinetic and pharmacodynamic results. KR-67607 also shares important chemical groups with ABT-384, another identified pseudo-irreversible HSD-1 inhibitor, and appears to share a binding mode to human HSD-1 with both SPI-62 and ABT-384 (see below).

[0153] The acid metabolite of ABT-384 is only 19% as potent an inhibitor of HSD-1 as ABT-384 in vitro. Furthermore, there is a structural basis for suggesting that the acid metabolite of ABT-384 is not a pseudo-irreversible HSD-1 inhibitor.

[0154] SPI-09 exhibited dose-proportional pharmacokinetics in cynomolgus monkeys over a wide range of single doses, which is not expected for pseudo-irreversible HSD-1 inhibitors. The pharmacokinetic behavior of ABT-384 in cynomolgus monkeys was similar to that in humans. Cynomolgus monkeys share a Pro-Cys motif important for allosteric regulation of human HSD-1 (see below), further supporting the cynomolgus monkey as a suitable species for characterizing pseudo-irreversible HSD-1 inhibitors.

[0155] Therefore, ABT-384 acid metabolite, SPI-09, and other HSD-1 inhibitors with shorter enzyme residence times are not classified as pseudo-irreversible inhibitors by in vitro enzyme kinetics.

[0156] Inhibitors that showed tachyphylaxis to adipose HSD-1 inhibition (BI-135585, AZD4017, AZD8329) were not classified as pseudo-irreversible inhibitors by in vitro enzyme kinetics.

[0157] However, some compounds (MK-0916, BMS-823778) that show clinical pharmacokinetics consistent with pseudo-irreversible inhibition are not classified as such by in vitro enzyme kinetics. A possible limitation of SPR is that the allosteric conformation of human HSD-1 in vivo (see below) cannot be maintained under the experimental conditions. To the extent that one or more binding modes of pseudo-irreversible HSD-1 inhibitors depend on the natural allosteric conformation of the enzyme, SPR may show long retention times for only some pseudo-irreversible HSD-1 inhibitors. BMS-823778 has a different binding mode to human HSD-1 than SPI-62, ABT-384 and KR-67607 (see below). MK-0916 and BMS-823778 have chemical structural similarities; the binding of these two molecules to human HSD-1 may be similar. Example 5. Pseudo-irreversible HSD-1 inhibitors identified by enzyme-inhibitor structure

[0158] Human HSD-1 appears to function as a tetramer. A primate-specific C-terminal proline (P)271 cysteine ​​(C)272 motif is located at the center of the tetramer and forms a reversible enzyme disulfide that modulates enzyme activity. Conformational flexibility of the tetramerization interface is coupled to structural changes in the enzyme active site, suggesting that the central P271-C272 motif may regulate enzyme activity. The two dimers associate through complementary interactions between pairs of enzyme carboxyl termini oriented in an antiparallel direction. Each carboxyl terminus in the HSD-1 tetramer is roughly perpendicular to the dimer 2-fold axis. This arrangement of the termini produces Long 4-helix bundle structure, which locates adjacent enzyme active sites at the top and bottom of the structure ( Figure 5Substrate (e.g., cortisone) binding induces a conformational change in the tetramer that provides enzyme specificity and protects the active site from bulk transfer, thereby facilitating hydride transfer.

[0159] Two structure-based models have been proposed for HSD-1 membrane interactions and subunit assembly in the ER lumen ( Figure 6 The highly invaginated membrane structure of the ER is consistent with a model in which tetramers spanning two lipid bilayers form compartments in which pseudo-irreversible inhibitors, after slowly dissociating from HSD-1, can rapidly reassociate with HSD-1 within the same tetramer to achieve long-term inhibition.

[0160] HSD-1 belongs to the short-chain dehydrogenase / reductase (SDR) enzyme family, which share a common reaction mechanism in which the active-site tyrosine (Y) acts as a catalytic acid, protonating the reactive ketone oxygen of the bound substrate. The active-site serine (S) stabilizes the orientation of the bound substrate. The conserved lysine (K) forms a hydrogen bond with the nicotinamide ribose of NADPH and lowers the pK of the Y hydroxyl group. a To facilitate proton transfer. In HSD-1, the catalytic triad is S170-Y183-K187. Many HSD-1 inhibitors interact with the catalytic triad, particularly S170 and Y183. Some HSD-1 inhibitors instead interact with the α-helical backbone near the catalytic triad.

[0161] It has been hypothesized that the formation of a ternary complex with the HSD-1 protein and the NADPH cofactor is a common feature of pseudo-irreversible inhibitors. Of the 39 HSD-1 inhibitors whose structures bound to HSD-1 have been deposited in the Protein Data Bank, a few appear to form such a ternary complex directly with NADPH. These can be further categorized according to three types of interactions: (1) hydrogen bonding between the amide nitrogen and the NADPH pyrophosphate (amide); (2) hydrogen bonding between the aromatic nitrogen and the NADPH pyrophosphate (aromatic); and (3) aromatic stacking interactions with the nicotinamide ring of NADPH (stacking). Interactions with the catalytic triad and nearby backbone are also summarized in Table 2 below. Table 2. Interactions with the catalytic triad and the backbone inhibitors PDB records NADP(H) S170 Y183 K187 skeleton Compound A 2irw Amide yes yes no no SAR184841 4hx5 Amide yes yes no no Compound B 3qqp Aromatic yes yes no no Compound C 2rbe stacking yes yes no no Compound D 3oq1 stacking no no no yes BMS-823778 5qii stacking yes yes no no

[0162] The association of one of these drugs with HSD-1 will be a bimolecular reaction, while dissociation will be a process in which the interaction of the drug and the catalytic cofactor NADPH with HSD-1 contributes to the activation energy barrier for dissociation. In a sense, the binding energy of NADPH to HSD-1 also holds the inhibitor to HSD-1. This results in the fast association and slow dissociation kinetics characteristic of pseudo-irreversible inhibitors.

[0163] The other 33 inhibitors for which structures are available for binding to HSD-1, including AZD4017 (PDB record 4hfr) and AZD8329 (PDB record 4p38), both of which show rapid tolerance to adipose HSD-1 inhibition, do not form ternary complexes that include NADPH or form them exclusively through water molecules. Water molecules may be sufficiently mobile in the active site that it is not currently predicted that complexes of HSD-1 inhibitors and NADPH through water molecules in the active site of human HSD-1 would confer the same advantages as amide, aromatic, and stacking interactions.

[0164] Figure 7 Compound A ((1s,3R,5S,7s)-4-(2-(4-methoxyphenoxy)-2-methylpropionamido)adamantane-1-carboxamide)) is useful because the molecular moiety that interacts with NADPH and the catalytic triad is identical to that in ABT-384 and KR-67607. Molecular docking was used to model the binding of SPI-62, ABT-384, and KR-67607 to HSD-1. The modeling suggests that these inhibitors form an amide-like ternary complex with NADPH in the active site. Together with SAR-184841 and Compound A, they are classified as pseudo-irreversible HSD-1 inhibitors.

[0165] SPI-62 displays different but similar interactions compared to other class members. For example, (a) the benzamide, but not the adamantanecarboxamide, interacts with NADPH pyrophosphate; and (b) the triazine ring, but not the amide ketone, interacts with S170 and Y183 ( Figure 10 BMS-823778 and other HSD-1 inhibitors also showed this triazine interaction with S170 and Y183.

[0166] Molecular docking models of the acid metabolites of SPI-62 and ABT-384 showed that the metabolites bind to benzoic acid or adamantane carboxylic acid in the opposite orientation away from NADPH pyrophosphate, providing the structural basis for the acid metabolites being much less potent HSD-1 inhibitors compared to the parent drugs.

[0167] The triazine ring of MK-0916 and BMS-823778 interacts with the nicotinamide ring of NADPH, S170, and Y183, which is the structural basis for their function as pseudo-irreversible HSD-1 inhibitors. Figure 9Established binding of BMS-823778 was shown. Using molecular docking techniques, the binding of MK-0916 was modeled to determine whether the binding mode was similar to that of BMS-823778. The model indicated that the inhibitor appears to form a stacking-like ternary complex with NADPH in the active site. Compounds C and D (PDB records 2rbe and 3oq1, Table 2) may also be pseudo-irreversible HSD-1 inhibitors. Compounds that form aromatic-like ternary complexes with NADPH in the HSD-1 active site (e.g., compound B; PDB record 3qqp) may be pseudo-irreversible inhibitors. Example 6. Evidence for HSD-1 Inhibitors as Potential Treatments for Glucocorticoid Excess

[0168] The hypothesis behind the use of HSD-1 inhibitors in patients with glucocorticoid overdose, whether endogenous (Cushing's syndrome and ACS) or exogenous (GC drugs), is that HSD-1 forms a large excess of intracellular GCs that can bind to intracellular GC and mineralocorticoid receptors as well as nongenomic receptors, thereby causing symptoms. HSD-1 inhibition could reduce intracellular GCs and therefore potentially alleviate symptoms in patients with Cushing's syndrome or ACS. It could also prevent or reverse many of the adverse effects associated with GC drug use, particularly in patients who rely on long-term GC use for the management of autoimmune diseases and other conditions.

[0169] Several independent lines of clinical and nonclinical evidence support the potential of HSD-1 inhibitors for the treatment of Cushing's syndrome or ACS, or as adjunctive therapy to GC in patients who require such agents.

[0170] HSD-1 activity is elevated in patients with Cushing's syndrome. The urinary HSD-1 ratio (a biomarker of hepatic HSD-1 activity) is 1.74 ± 0.24 in patients with Cushing's disease, 3.95 ± 0.69 in patients with ectopic ACTH secretion, and 1.7 (median) in patients with adrenal Cushing's syndrome, compared with 1.21 ± 0.06 in healthy adults. The elevated HSD-1 ratio is thought to result from the induction of HSD-1 by cortisol.

[0171] Despite very high 24-hour urinary free cortisol, patients with Cushing's syndrome and constitutionally low HSD-1 activity do not display symptoms associated with hypercortisolism. For example, a 20-year-old woman developed amenorrhea, the androgenic symptom of Cushing's disease, and exhibited no sequelae of hypercortisolism. Her urinary free cortisol was variously 831 nmol / 24 hours and 1049 nmol / 24 hours, and her urinary HSD-1 ratio was 0.66. After transsphenoidal adenoma resection, she resumed menstruation, and her circulating and urinary cortisol levels returned to normal. In another example, a 55-year-old woman had an unexpectedly discovered adrenal tumor. She showed no signs of Cushing's syndrome, insulin resistance, hypertension, or dyslipidemia. Her urinary free cortisol was 1149 nmol / 24 hours, and her urinary HSD-1 ratio was variously 0.61 to 0.66. After adrenalectomy, high-dose glucocorticoid therapy is initially required to prevent adrenal insufficiency.

[0172] A pilot open-label clinical trial of an HSD-1 inhibitor (S-707106) in patients with hypercortisolism (11 with ACS and 4 with Cushing's syndrome) showed positive trends in glycemic control and body habitus. At 24 weeks, participants experienced a mean weight loss of 1.6 kg, a 2.5% decrease in body fat percentage, and a 2.4% increase in body muscle percentage. The area under the glucose curve after an oral glucose tolerance test was reduced, primarily in obese subjects.

[0173] In a cohort of healthy adult men, those given 20 mg of prednisolone and an HSD-1 inhibitor (AZD4017) for 7 consecutive days demonstrated reduced resistance to insulin sensitivity, increased triglycerides, elevated nocturnal blood pressure, decreased biomarkers of bone formation, and increased biomarkers of bone resorption during a euglycemic clamp compared with those given prednisolone alone.

[0174] Clinical trial results using various HSD-1 inhibitors support their efficacy in treating certain common chronic diseases and conditions associated with GC excess, including INCB-13739 for diabetes, RO5093151 for non-alcoholic fatty liver disease, and AZD4017 for impaired wound healing. HSD-1 inhibitors in some clinical trials have also been associated with a 1-2 kg weight loss at 12 weeks compared to placebo. Other clinical trials of HSD-1 inhibitors have demonstrated a lack of efficacy, even with adequate doses and positive results with active controls (e.g., ABT-384 for dementia). However, other clinical trials of HSD-1 inhibitors have demonstrated a lack of efficacy, perhaps due to insufficient treatment periods or exclusion of patients with GC excess, such as BI-187004 for diabetes. Diabetes, non-alcoholic fatty liver disease, impaired wound healing, obesity, and dementia are complex conditions in which excess cortisol is only one of multiple etiological factors and is not applicable to all patients. HSD-1 inhibitors might be expected to be particularly beneficial for patients with GC excess, for whom such treatment is specifically targeted at the primary cause of their illness. This may be the case even for conditions for which previous clinical trials of HSD-1 inhibitors have been negative, such as cognitive impairment.

[0175] HSD-1 knockout mice are resistant to multiple adverse effects of exogenously administered corticosterone (CORT; the murine equivalent of Cortisol). CORT inhibits HPA axis activity, as evidenced by adrenal atrophy, similarly in knockout and control mice. Compared to control mice, knockout mice showed essentially no effect of corticosterone on blood pressure and hepatic steatosis, and the effects of CORT on insulin resistance, obesity, muscle atrophy, and skin atrophy were greatly reduced. Knockout mice were almost completely resistant to the adverse effects of CORT on trabecular bone structure.

[0176] HSD-1 inhibitors have demonstrated the ability to block or reverse exogenously administered GCs in animal models. Abbott HSD-1 inhibitors blocked the adverse skeletal effects of GC administration in rats. Femoral head necrosis induced by the mycotoxins patulin and prednisolone was ameliorated by administration of HSD-1 inhibitors, demonstrating improvements in bone microarchitecture and density. Both carbenoxolone and PF-915275 prevented GC-induced wound healing impairment in mice. In rabbits, glycyrrhizin partially prevented the increase in intraocular pressure associated with intravitreal triamcinolone acetonide. Example 7. Supporting evidence specific to SPI-62

[0177] Clinical and nonclinical evidence supports the specific potential of SPI-62 for the treatment of Cushing's syndrome or ACS, or as an adjunct therapy to GC in patients who require such an agent.

[0178] Analysis of covariance was performed to analyze total cholesterol (TC), glucose, glycated hemoglobin (HbA1c), and triglycerides (TG) in patients with painful diabetic peripheral neuropathy who received daily SPI-62 or placebo, with baseline values ​​as covariates and a baseline*treatment interaction term. Data were from Study 3662-CL-0049, a Phase 2 randomized, double-blind, placebo- and active-controlled clinical trial designed to evaluate the safety and efficacy of SPI-62 in subjects with painful diabetic peripheral neuropathy.

[0179] Compared with placebo, SPI-62 was associated with lower baseline-corrected values ​​for TC, glucose, HbA1c, and TG at Week 6 / end of study (EOT). Within 2 weeks after discontinuation of study drug administration (Week 8 / end of study (EOS)), the magnitude of the differences in TC, glucose, and TG decreased, but HbA1c increased. A treatment*baseline interaction was observed at Week 6 / EOT for TC and HbA1c, such that patients with higher baseline values ​​showed, on average, greater differences between SPI-62 and placebo, but not for glucose or TG. Figure 11 Overall, SPI-62 was associated with favorable changes in TC, glucose, HbA1c, and TG in patients with PDPN. These analyses strengthen confidence in SPI-62's potential to control hyperglycemia and dyslipidemia. Patients with elevated TC or HbA1c values ​​may particularly benefit from SPI-62 therapy.

[0180] The magnitude of the effects of SPI-62, a pseudo-irreversible HSD-1 inhibitor, on HbA1c, TC, and TG (Table 3) were numerically greater than those reported for other HSD-1 inhibitors in other clinical trials. Table 3. Effects of HSD-1 inhibitors on HbA1c, TC, and TG.

[0181] To demonstrate that SPI-62 reduces the adverse effects of corticosterone (CORT) in mice, C57BL / 6 male mice (7 weeks old; n=14 / group) were administered CORT (100 mg / mL in drinking water) and SPI-62 (by gavage in 0.5% HPMC; 0 mg / kg / day, 1 mg / kg / day, or 10 mg / kg / day or 10 mg / kg twice a day) for 35 days. The control group did not receive CORT or SPI-62. Body weight was assessed daily, and food consumption was assessed twice a week. Whole body muscle and fat mass were measured on days 0, 14, and 28 using an EchoMRI-130H body composition analyzer. Blood samples for fasting glucose and insulin were collected on days 1 (pre-dose), 15, 29, and 35. An open field test was performed on day 22. A grip strength test was performed on day 28. After sacrifice on day 36, gonads, subcutaneous, retroperitoneal and mesenteric fat, quadriceps femoris and tibialis anterior muscles were dissected and weighed, and the skin was fixed in formalin and embedded in paraffin.

[0182] CORT causes increased food consumption, which SPI-62 appears to normalize. CORT-treated mice had reduced weight gain over a 2-week period, after which weight gain accelerated. SPI-62 prevented the accelerated weight gain. The effects of CORT on dermal thickness and structure were less pronounced in mice that also received SPI-62. No effects of CORT or SPI-62 were observed in the open field test. SPI-62 prevented the adverse effects of CORT of insulin resistance, increased adiposity, skeletal muscle atrophy, and decreased grip strength. SPI-62 prevented several adverse effects of CORT in mice, suggesting that blocking local intracellular glucocorticoid activation in target tissues by HSD-1 inhibitors can mitigate glucocorticoid toxicity. See Tables 4 to 9 and Figure 12 and Figure 13 . Table 4. Insulin resistance in mice administered CORT and SPI-62 Mice (n=14 / group) received corticosterone and SPI-62 or vehicle in drinking water by gavage for 35 days. Data were analyzed by ANCOVA with baseline as a covariate. a P < 0.05 versus vehicle + water; b P < 0.05 vs. vehicle + CORT Table 5. Whole body muscle and fat content in mice administered CORT and SPI-62 Mice (n=14 / group) received corticosterone and SPI-62 or vehicle in drinking water by gavage for 35 days. Data were analyzed by ANCOVA with baseline as a covariate. a P < 0.05 versus vehicle + water; b P < 0.05 vs. vehicle + CORT Table 6. Postmortem (day 36) fat accumulation weight in mice administered CORT and SPI-62 Mice (n=14 / group) received corticosterone and SPI-62 or vehicle in drinking water by gavage for 35 days. Data were analyzed by ANOVA. a P < 0.05 versus vehicle + water; b P < 0.05 vs. vehicle + CORT Table 7. Postmortem (day 36) muscle weight in mice administered CORT and SPI-62 Mice (n=14 / group) received corticosterone and SPI-62 or vehicle in the drinking water by gavage for 35 days. Data were analyzed by ANOVA. a P < 0.05 versus vehicle + water; b P < 0.05 vs. vehicle + CORT Table 8. Group mean [standard deviation] of food consumption observed in mice administered CORT and SPI-62. Mice (n=7 co-housed pairs / group) received corticosterone and SPI-62 or vehicle in drinking water by gavage for 35 days. No pre-specified or hypothesis testing was performed (see Methods). Table 9. Group means and standard deviations of body weight observed at baseline and on days 15, 29, and 35 in mice administered CORT and SPI-62. Mice (n=14 / group) received corticosterone and SPI-62 or vehicle in drinking water by gavage for 35 days. No prespecified or hypothesis testing was performed. Example 8. Development of a PK-Adipose PD Model

[0183] SPI-62 was administered daily for 14 days to male and non-menstrual female subjects with type 2 diabetes aged 18 to 65 years and with a body mass index between 30.0 and 45.0. In addition to the 6 subjects described in Example 1 who received SPI-62 1 mg, 3 mg, or 6 mg for 14 days, 6 subjects received SPI-62 1 mg, 2 mg, 3 mg, or 10 mg for 5 to 8 days. For at least 4 hours before and during the selected dosing interval, perfusate T1 (M Dialysis, Stockholm, Sweden) + 1 μg / mL D8 cortisone ([2,2,4,6,6,9,12,12-]) in 0.5% ethanol USP was administered via a microdialysis catheter (63 microdialysis catheter, M Dialysis, Stockholm, Sweden) at a rate of 1 μL / min. 2 [H8] cortisone (MilliporeSigma, Miamisburg, OH) was continuously infused into subcutaneous abdominal adipose tissue. Adipose dialysate was collected at two-hour intervals (0-2, 2-4, 4-6, 6-8, 8-10, 20-22, and 22-24 hours after SPI-62 dosing) and analyzed for D8 cortisone and D8 cortisol. The D8 cortisol mole percentage fraction (MPF) was calculated as: ([2, 2, 4, 6, 6, 9, 12, 12- 2 H8]Cortisol*368.51) / ([2,2,4,6,6,9,12,12- 2 H8] cortisone * 370.52), where 368.51 and 370.52 are the molar masses of D8 cortisone and D8 cortisol respectively. The percentage of adipose HSD-1 inhibition was calculated as: 100*(1-(MPF t / MPF 基线 The time of sample (t) was considered the midpoint of the collection interval. A more sensitive assay for D8 Cortisol was used to enable quantification of adipose HSD-1 inhibition >95%.

[0184] like Figure 14 The data were fitted to a target-mediated drug disposition (TMDD) model, in which SPI-62 is absorbed at a first-order rate constant (K a ) Arrive at the center room (C p , V 中心 ) can be distributed to the peripheral chamber (C t , V 外周 ), eliminated from the system (CL) or with a second-order association rate constant (k on ) binds to the target site (R) to form the SPI-62-R complex. This complex will dissociate at a first-order rate constant (k off ) dissociates back into free drug and free target. In addition, three sequential and equal first-order conversion rate constants (KTR ) to characterize the movement of SPI-62 from the absorption site (i.e., the accumulation compartment) to the central compartment. The model also includes the adipose interstitial fluid compartment and the adipose tissue cell compartment, where the transport of SPI-62 molecules between the two compartments is determined by their permeability (PS). In addition, the TMDD process occurs in adipose tissue: SPI-62 molecules in the adipose tissue cell compartment can be bound at a second-order binding rate constant (k on ) and target sites (i.e. HSD-1 expressed in adipocytes, R TA ) to form the SPI-62-R complex. Since the SPI-62 concentration in the adipose dialysate is the unbound concentration sampled using microdialysis, the unbound fraction (fu) was incorporated into the model to account for this. Finally, the complete PK / PD model structure included the inhibitory I max Model to relate SPI-62 adipose concentration to adipose HSD-1 activity.

[0185] The key parameters estimated in the model include: association rate constant (k on )1.44nM -1 h -1 , the dissociation rate constant (k off )0.264h -1 , the total target volume in the central chamber (R TOT )7840nM, the total target amount in the fat compartment (R TA ) 671 nM, the fat-free concentration that achieves 50% HSD-1 inhibition (IC 50 )23.4pM, and Hill coefficient (γ)1.42.

[0186] Estimated K d (k off / k on ) was 183 pM, which is lower than the measured K of SPI-62 for human HSD-1 expressed in CHO cells. i The K of SPI-62 for purified human HSD-1 was 12.6 nM, 69-fold lower than that of SPI-62. i 5.3 nM, 29-fold lower. Estimated IC 50 The measured IC values ​​of SPI-62 for purified human HSD-1 were compared 50 These two differences indicate the unexpectedly high potency of SPI-62 against HSD-1 in human adipose tissue, consistent with the lack of adipose tachyphylaxis resulting from the highly effective competitive binding of SPI-62 to HSD-1 relative to accumulated cortisone (i.e., an HSD-1 substrate).

[0187] Estimated total target volume (R TOT +R TA) corresponds to 3.6 mg of SPI-62, which is consistent with the dose range in which nonlinear PK is observed after a single dose of SPI-62. The Hill coefficient indicates that SPI-62 binds to human HSD-1 with moderate positive cooperativity. Example 9. Potential Advantages of Pseudo-Irreversible HSD-1 Inhibitors

[0188] This paper describes a key finding: SPI-62 shows no tachyphylaxis to adipose HSD-1 inhibition. This tachyphylaxis has been previously reported for three other HSD-1 inhibitors (AZD4017, AZD8329, and BI-135585) and may be considered a class effect. BI-187004, identified as a pseudo-irreversible HSD-1 inhibitor based on fast-binding, slow-dissociating in vitro enzyme kinetics, shows only limited tachyphylaxis to adipose HSD-1 inhibition. SPI-62 is the first HSD-1 inhibitor demonstrated to lack tachyphylaxis to adipose HSD-1. Structural modeling, in which SPI-62 and certain other HSD-1 inhibitors form a ternary complex with NADPH at the human HSD-1 active site, predicts that members of this genus of pseudo-irreversible HSD-1 inhibitors do not show tachyphylaxis to adipose HSD-1 inhibition. Given the relative importance of adipose HSD-1 in regulating cardiometabolic processes that correspond to the prevalence of GC excess, it is anticipated that pseudo-irreversible inhibitors may offer clinical advantages over other HSD-1 inhibitors in areas such as glycemic and lipid control, particularly in patients with GC excess. For example, animal model data from BI-187004 suggest that glucose-lowering efficacy is dependent on sustained >90% inhibition of adipose HSD-1. 14,15 Evidence supporting this finding also comes from SPI-62, which has limitations, including varying durations of administration in separate clinical trials relative to the maximal reported effects of HSD-1 inhibitors on HbA1c, cholesterol, and triglycerides.

[0189] Pseudo-irreversible HSD-1 inhibitors may have other advantages over other HSD-1 inhibitors. For example, due to their long-lasting pharmacological effects, pseudo-irreversible HSD-1 inhibitors are more amenable to lower daily doses, including cumulative formulations, and are less likely to show decreased efficacy due to poor patient compliance. Furthermore, HSD-1 in the human body appears to be fully occupied by approximately 3 mg of the potent small-molecule inhibitor. Because pseudo-irreversible inhibitors, once bound, are only slowly released from HSD-1, low chronic doses are possible. Several pseudo-irreversible HSD-1 inhibitors (e.g., SPI-62, ABT-384, MK-0736, and MK-0916) have effective doses ranging below 10 mg per day. In contrast, other HSD-1 inhibitors (e.g., S-707106, AZD4017, INCB-13739, and RO5093151) require daily doses of 100 mg or more to show efficacy. At higher doses, the likelihood of certain types of side effects (e.g., hepatotoxicity, noted with AZD4017) increases.

[0190] In summary, this disclosure describes the discovery that a genus of HSD-1 inhibitors sharing certain common properties may have clinical advantages, particularly for patients with GC excess.

[0191] The various embodiments described above can be combined to provide additional embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification and / or listed in the application data sheet are incorporated herein by reference in their entirety. If it is desired to employ concepts from various patents, applications, and publications to provide yet additional embodiments, aspects of these embodiments may be modified.

[0192] These and other changes can be made to the embodiments in light of the above detailed description. Generally, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and claims, but should be construed to include all possible embodiments, along with the full scope of equivalents to which such claims are entitled. Therefore, these claims are not limited by this disclosure.

Claims

1. A method for treating glucocorticoid overdose in a patient in need thereof, the method comprising administering to the patient a pseudo-irreversible HSD-1 inhibitor.

2. A method for ameliorating or preventing symptoms of glucocorticoid overdose in a patient in need thereof, the method comprising administering to the patient a pseudo-irreversible HSD-1 inhibitor.

3. A method for reducing urinary tetrahydrocortisol levels in a patient with glucocorticoid overdose, the method comprising administering to the patient a pseudo-irreversible HSD-1 inhibitor, wherein the urinary tetrahydrocortisol levels are elevated compared to asymptomatic patients.

4. method as claimed in claim 2, wherein the excessive symptoms of these glucocorticoids comprise cardiovascular, metabolism, immunity, skeleton, muscle, skin, eye, spirit, cognition, circadian rhythm or steady-state symptoms.

5. The method of claim 4, wherein the cardiovascular symptoms are selected from hypertension (including lack of nocturnal blood pressure drop), atherosclerosis, endothelial dysfunction, prothrombotic state, coronary artery disease, heart failure and stroke.

6. The method of claim 4, wherein the metabolic symptoms are selected from obesity, glucose intolerance, insulin resistance, diabetes, and dyslipidemia (including hypercholesterolemia and hypertriglyceridemia).

7. The method of claim 4, wherein the immune symptoms are selected from infections (including opportunistic infections) and sepsis.

8. The method of claim 4, wherein the bone symptoms are selected from osteoporosis, osteonecrosis, osteopenia, hypocalcemia (through decreased absorption or increased renal elimination or effects on vitamin D and PTH), linear bone growth (stature), and fractures (including low impact or compression fractures).

9. The method of claim 4, wherein the muscle symptoms are selected from muscle atrophy and muscle weakness.

10. The method of claim 4, wherein the dermatological symptoms are selected from the group consisting of impaired wound healing, thin or fragile skin, abnormal accumulation of subcutaneous fat, plethora of red blood cells, purple striae, acanthosis nigricans, hyperpigmentation, and easy bruising.

11. The method of claim 4, wherein the ocular symptoms are selected from the group consisting of increased intraocular pressure, glaucoma, proptosis, and cataracts.

12. The method of claim 4, wherein the psychiatric symptoms are selected from depression, anxiety, hypomania, mania and psychosis.

13. The method of claim 4, wherein the cognitive symptoms are selected from impairments of memory, visuospatial processing, reasoning, verbal learning, and language performance.

14. The method of claim 4, wherein the circadian rhythm symptoms are selected from the group consisting of insomnia, daytime fatigue, sleep apnea, sleep fragmentation, increased nocturnal motor activity, and REM sleep disturbances.

15. The method of claim 4, wherein the homeostatic symptoms are selected from hypokalemia, hypernatremia, hypophosphatemia, hypercalciuria, growth hormone suppression, and thyroid disease (including hypothyroidism and hyperthyroidism).

16. The method of any one of claims 1 to 15, wherein the pseudo-irreversible HSD-1 inhibitor does not show tachyphylaxis to human adipose HSD-1 inhibition.

17. The method of claim 16, wherein: The HSD-1 inhibitor is selected from SPI-62 and BI-187004, or a pharmaceutically acceptable salt thereof.

18. The method of any one of claims 1 to 15, wherein the HSD-1 inhibitor is characterized by human pharmacokinetics consistent with target mediated drug disposition.

19. The method of claim 18, wherein the HSD-1 inhibitor is selected from SPI-62, ABT-384, MK-0736, MK-0916, BMS-823778, UE-2343, BI-187004 and AMG-221, or a pharmaceutically acceptable salt thereof.

20. The method of claim 18, wherein the plasma exposure of the HSD-1 inhibitor is less than dose proportional after a single low dose and is dose proportional after multiple low doses.

21. The method of claim 20, wherein the doses are 10 mg or less.

22. The method of claim 21, wherein the doses are 6 mg or less.

23. The method of claim 21, wherein the doses are 4 mg or less.

24. The method of any one of claims 1-15, wherein the HSD-1 inhibitor is characterized by human pharmacodynamics consistent with target mediated drug disposition.

25. The method of claim 24, wherein the HSD-1 inhibitor is selected from SPI-62 and ABT-384, or a pharmaceutically acceptable salt thereof.

26. The method of claim 24, wherein the pharmacodynamic half-life of the HSD-1 inhibitor on hepatic HSD-1 inhibition is prolonged compared to its pharmacokinetic half-life.

27. The method of claim 26, wherein the HSD-1 inhibitor has a pharmacodynamic half-life of at least 1 week for inhibition of human liver HSD-1.

28. The method of claim 27, wherein the pharmacodynamic half-life is at least 2 weeks.

29. The method of claim 27, wherein the pharmacodynamic half-life is at least 4 weeks.

30. The method of any one of claims 1 to 15, wherein the HSD-1 inhibitor is characterized by fast association, slow dissociation binding kinetics to human HSD-1.

31. The method of claim 30, wherein the HSD-1 inhibitor has a residence time of at least about 500 seconds.

32. The method of claim 30, wherein the HSD-1 inhibitor is selected from SPI-62, ABT-384, KR-67607, UE-2343 and BI-187004, or a pharmaceutically acceptable salt thereof.

33. The method of any one of claims 1 to 15, wherein the HSD-1 inhibitor forms a hydrogen bond with the pyrophosphate of NADPH at the human HSD-1 active site.

34. The method of claim 33, wherein the HSD-1 inhibitor is selected from SPI-62, ABT-384, KR-67607, SAR-184841, Compound A and Compound B, or a pharmaceutically acceptable salt thereof.

35. The method of any one of claims 1 to 15, wherein the HSD-1 inhibitor forms an aromatic stacking interaction with NADPH at the human HSD-1 active site.

36. The method of claim 35, wherein the HSD-1 inhibitor is selected from BMS-823778, MK-0916, Compound C, Compound D, or a pharmaceutically acceptable salt thereof.

37. A method for ameliorating or preventing symptoms of glucocorticoid overdose in a patient in need thereof, the method comprising administering to the patient a pseudo-irreversible HSD-1 inhibitor that is a brain penetrant. A method for ameliorating or preventing symptoms of glucocorticoid overdose in a patient in need thereof, the method comprising administering to the patient a pseudo-irreversible HSD-1 inhibitor.

38. The method of claim 37, wherein the symptoms are selected from psychiatric, cognitive or circadian rhythm symptoms.

39. The method of claim 38, wherein: The psychiatric symptoms are selected from depression, anxiety, hypomania, mania, and psychosis; or The cognitive symptoms are selected from impairments in memory, visuospatial processing, reasoning, verbal learning, and language performance; or These circadian rhythm symptoms are selected from insomnia, daytime fatigue, sleep apnea, sleep fragmentation, increased nocturnal motor activity, and REM sleep abnormalities.

40. The method of claim 37, wherein the pseudo-irreversible HSD-1 inhibitor does not exhibit tachyphylaxis to human adipose HSD-1 inhibition.

41. The method of claim 40, wherein the HSD-1 inhibitor is SPI-62.

42. The method of claim 37, wherein the HSD-1 inhibitor exhibits human pharmacokinetics consistent with target mediated drug disposition.

43. The method of claim 42, wherein the HSD-1 inhibitor is selected from SPI-62, ABT-384 and UE-2343, or a pharmaceutically acceptable salt thereof.

44. The method of claim 37, wherein the HSD-1 inhibitor is characterized by human pharmacodynamics consistent with target mediated drug disposition.

45. The method of claim 44, wherein the HSD-1 inhibitor is selected from SPI-62 and ABT-384, or a pharmaceutically acceptable salt thereof.

46. ​​The method of claim 37, wherein the HSD-1 inhibitor exhibits fast association, slow dissociation binding kinetics to human HSD-1.

47. The method of claim 46, wherein the HSD-1 inhibitor is selected from SPI-62, ABT-384 and UE-2343, or a pharmaceutically acceptable salt thereof.

48. The method of claim 37, wherein the HSD-1 inhibitor forms a hydrogen bond with the pyrophosphate of NADPH in the human HSD-1 active site.

49. The method of claim 48, wherein the HSD-1 inhibitor is selected from SPI-62 and ABT-384, or a pharmaceutically acceptable salt thereof.

50. The method of claim 37, wherein the HSD-1 inhibitor forms an aromatic stacking interaction with NADPH at the human HSD-1 active site.

51. The method of any one of claims 1 to 50, further comprising administering a glucocorticoid drug to the patient.

52. The method of claim 51, wherein the HSD-1 inhibitor is administered in a fixed dose combination with a glucocorticoid drug.

53. The method of claim 51, wherein the HSD-1 inhibitor and glucocorticoid drug are co-packaged for separate administration.

54. The method of claim 51, wherein the HSD-1 inhibitor and the glucocorticoid drug are administered and packaged separately.

55. The method of any one of claims 51 to 54, wherein the glucocorticoid drug is selected from prednisolone, methylprednisolone, dexamethasone, hydrocortisone, budesonide, deflazacort, beclomethasone, ciclesonide, fluticasone, mometasone, triamcinolone acetonide, flunisone, clobetasol, betamethasone, fluocinolone acetonide, fluocinolone acetonide, clocortolone, halobetasol, desoximetasone, desonide, halcinonide, prednicarbate, diflorasone, amcinonide, alclomethasone, difluprednate, loteprednol, fluorometholone, rimexolone and medrysone, or a pharmaceutically acceptable salt or ester derivative thereof.

56. The method of any one of claims 1 to 50, wherein the patient has a tumor that secretes ACTH or CRH.

57. The method of any one of claims 1 to 50, wherein the patient has a Cortisol-secreting tumor.

58. The method of any one of claims 1 to 57, wherein the HSD-1 inhibitor is SPI-62 or a pharmaceutically acceptable salt thereof.

59. The method of any one of claims 1 to 58, wherein the HSD-1 inhibitor is administered orally.

60. The method of any one of claims 1 to 58, wherein the HSD-1 inhibitor is administered intravenously.

61. The method of any one of claims 1 to 58, wherein the HSD-1 inhibitor is administered intramuscularly or subcutaneously.

62. The method of any one of claims 1 to 58, wherein the HSD-1 inhibitor is administered by inhalation or intranasally.

63. The method of any one of claims 1 to 58, wherein the HSD-1 inhibitor is administered ophthalmically.

64. The method of any one of claims 1 to 58, wherein the HSD-1 inhibitor is administered topically.

65. The method of any one of claims 1 to 15, wherein the HSD-1 inhibitor has a K of d Lower than K i .

66. The method of claim 65, wherein the HSD-1 inhibitor has a K d K i At least 60 times lower.

67. The method of any one of claims 1 to 15, wherein the estimated body fat IC of the HSD-1 inhibitor is 50 Lower than the in vitro measured value of this HSD-1 inhibitor.

68. The method of claim 67, wherein the estimated body fat IC 50 At least 700 times lower than the in vitro measurements.

69. The method of any one of claims 65 to 68, wherein the HSD-1 inhibitor is SPI-62 or a pharmaceutically acceptable salt thereof.

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