Use of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid in the treatment of diabetes and prediabetes

Abstract

The method and composition for treating diabetes or prediabetes comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt to a subject diagnosed with diabetes or prediabetes.In some embodiments, administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt to a subject diagnosed with diabetes or prediabetes is effective in reducing one or more of HbA1c level, fasting plasma glucose, 2-hour oral glucose tolerance test (OGTT) result value, and random plasma glucose level.(S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt can optionally be administered in combination with a hypoglycemic agent.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 485,624, filed February 17, 2023, the entire contents of which are incorporated herein by reference.

[0002] Technical Field Treatment of diabetes and prediabetes with (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. [Background technology]

[0003] background According to the World Health Organization, diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. Insulin regulates (lowers) blood glucose levels. It is a peptide hormone produced by beta cells in the pancreatic islets. Insulin regulates carbohydrate, lipid, and protein metabolism by promoting glucose uptake from the blood into fat cells, liver cells, and skeletal muscle cells. Pancreatic beta cells (β cells) are sensitive to blood glucose levels. In non-diabetic individuals, pancreatic beta cells secrete insulin into the blood when blood glucose levels are high, but insulin secretion is suppressed when glucose levels are low. Pancreatic alpha cells secrete another peptide hormone, glucagon, into the blood to increase blood glucose levels, but in the opposite manner: increased secretion when blood glucose levels are low and decreased secretion when glucose levels are high. The secretion of insulin and glucagon into the blood in response to blood glucose levels is the primary mechanism contributing to maintaining extracellular glucose levels within a narrow range.

[0004] Hyperglycemia, or high blood sugar, is a common consequence of uncontrolled diabetes and, over time, can cause serious damage to many systems in the body, particularly nerves and blood vessels. According to the World Health Organization, the number of people with diabetes increased from 108 million in 1980 to 422 million in 2014. In 2014, 8.5% of adults aged 18 and over had diabetes. In 2012, diabetes was the direct cause of 1.5 million deaths, and high blood glucose contributed to an additional 2.2 million deaths. Diabetes is a leading cause of blindness, kidney failure, heart attack, stroke, and lower-limb amputation. Adults with diabetes have a two- to three-fold increased risk of heart attack and stroke. Neuropathy (nerve damage) in the feet, combined with reduced blood flow, increases the likelihood of foot ulcers, infection, and ultimately the need for limb amputation. Diabetes is one of the leading causes of kidney failure.

[0005] Type 1 diabetes (formerly known as insulin-dependent, juvenile, or childhood-onset) is characterized by insufficient insulin production and generally requires daily insulin administration. The majority of cases of type 1 diabetes are primarily due to the destruction of pancreatic islet beta cells. Patients with type 1 diabetes are prone to ketoacidosis. Symptoms of type 1 diabetes include excessive urine production (polyuria), dry mouth (polydipsia), persistent hunger, weight loss, vision changes, and fatigue. These symptoms can occur suddenly. Type 2 diabetes (formerly known as non-insulin-dependent or adult-onset) results from the body's inefficient use of insulin. The majority of people with diabetes worldwide have type 2 diabetes. Type 2 diabetes is associated with overweight and physical inactivity. Symptoms can be similar to those of type 1 diabetes but are often milder. Sleep apnea is associated with an increased risk of developing type 2 diabetes. See Botros et al., Amer. J. Med., 122(12), 1122-1127 (2009). More than 50% of patients with type 2 diabetes have sleep apnea. Until recently, type 2 diabetes was seen only in adults, but it is now occurring with increasing frequency in children. In type 1 diabetes, 70% of pancreatic beta cells are destroyed, while in type 2 diabetes, 40-60% of pancreatic beta cells are destroyed at the time of diagnosis. Al-Kuraishy et al., Int J Prev Med. 2021 Feb 24;12:19.

[0006] Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) (collectively referred to herein as "pre-diabetes") are intermediate states in the transition from normal to diabetes. IFG and IGT are not interchangeable and represent different abnormalities in glucose regulation, one during the fasting state and one after a meal. People with IGT or IFG are at increased risk of developing type 2 diabetes, but they do not necessarily progress to it.

[0007] According to the American Diabetes Association guidelines, the diagnostic criteria for diabetes include four options: a fasting plasma glucose level of 126 mg / dL or higher, a plasma glucose level of 200 mg / dL or higher on a 2-hour oral glucose tolerance test (OGTT), an HbA1c level of 6.5% or higher, or a random plasma glucose level of 200 mg / dL or higher in individuals with hyperglycemic symptoms or a hyperglycemic crisis. Prediabetes is defined as a fasting glucose level of 100 mg / dL to 125 mg / dL, a plasma glucose level of 140 mg / dL to 199 mg / dL on a 2-hour OGTT, or an HbA1c level of 5.7% to 6.4%. Prediabetes can be considered a major risk factor for the development of type 2 diabetes, cardiovascular disease, and mortality.

[0008] HbA1c, a product of nonenzymatic glycation of hemoglobin B chains, can be considered an important parameter in monitoring diabetes treatment. HbA1c levels depend on blood glucose levels and the lifespan of red blood cells in the blood. HbA1c levels generally reflect the patient's average blood glucose levels over the 4 to 12 weeks prior to blood collection and testing. Diabetic patients with well-controlled HbA1c levels (i.e., less than 6.5% of total hemoglobin in the sample) over long-term treatment are generally better protected from diabetic microangiopathy. Available diabetes treatments can improve HbA1c levels by approximately 1.0 to 1.5% on average in diabetic patients. However, this reduction in HbA1c levels may not be sufficient to bring all diabetic patients into the desired target range (HbA1c <7.0%, preferably <6.5%, and more preferably <6%).

[0009] In addition to improving HbA1c levels, another recommended treatment goal for patients with type 2 diabetes is to achieve normal or as close to normal as possible fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels. The desired target range for preprandial (fasting) plasma glucose can be, for example, 90-130 mg / dL or <110 mg / dL, and the desired target range for 2-hour postprandial plasma glucose can be, for example, <180 mg / dL or <140 mg / dL.

[0010] Dietary therapy and exercise therapy are often considered essential in the treatment of diabetes. When these therapies do not adequately control the patient's condition (especially blood glucose levels), oral or parenteral antidiabetic drugs can be used to treat diabetes. Conventional antidiabetic or hypoglycemic drugs include, but are not limited to, biguanides, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, thiazolidinediones, meglitinides (also known as glinides), alpha-glucosidase blockers, GLP-1 and GLP-1 analogs, and insulin and insulin analogs.

[0011] Although intensive treatment of hyperglycemia can reduce the incidence of chronic damage, existing antihyperglycemic therapies have limitations in long-term efficacy, tolerability, and inconvenient administration, which contribute to the fact that many diabetic patients remain undertreated. The use of conventional hypoglycemic drugs can be associated with various adverse effects. For example, metformin can be associated with lactic acidosis or gastrointestinal side effects; sulfonylureas, meglitinides (glinides), and insulin or insulin analogs can be associated with hypoglycemia or weight gain; thiazolidinediones can be associated with edema, bone fractures, weight gain, or effects on heart failure / cardiac function; and alpha-glucosidase blockers and GLP-1 or GLP-1 analogs can be associated with gastrointestinal adverse effects (e.g., dyspepsia, flatulence or diarrhea, or nausea or vomiting). There is a continuing need for improved antihyperglycemic therapies in the treatment of metabolic diseases.

[0012] Vigabatrin is a gamma-aminobutyric acid aminotransferase (GABA-AT) inhibitor used to treat treatment-resistant epilepsy and infantile spasms. Vigabatrin is associated with several potentially serious side effects. Its use is limited due to the possibility of retinal toxicity and subsequent visual field loss. (1S,3S)-3-aminodifluoromethylenyl-1-cyclopentanoic acid (also known as CPP-115) is a GABA-AT inhibitor that inactivates GABA-AT 186-fold more efficiently than vigabatrin. Preclinical data on CPP-115 have reportedly demonstrated comparable pharmacokinetics, improved tolerability, and a more favorable toxicity profile compared to vigabatrin at significantly lower drug doses. See Prescot et al., Neuropsychopharmacology (2018) 43, 646-654. See also U.S. Patent No. 9,993,449, incorporated herein by reference. (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (also known as OV329) is a GABA-AT inhibitor that has been shown to be 9.8 times more effective as a GABA-AT inactivator than CPP-115. Id. Summary of the Invention

[0013] overview Methods and compositions for treating diabetes and prediabetes are provided. In some embodiments, the method for treating diabetes and prediabetes comprises administering an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt to a subject in need thereof. In some embodiments, the composition for treating diabetes and prediabetes, comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, is administered to a subject in need thereof. In some embodiments, the method for treating diabetes and prediabetes comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt to a subject in need thereof, thereby improving one or more symptoms of diabetes and prediabetes in the subject. In some embodiments, a method for treating diabetes and prediabetes comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, resulting in an improvement in the symptoms of diabetes and prediabetes in the subject the day after administration of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is about 0.01 mg to about 750 mg. In some embodiments, an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject once a day, twice a day, three times a day, or four times a day.

[0014] In some embodiments, a method for treating diabetes or prediabetes comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to reduce one or more of HbA1c levels, fasting plasma glucose, 2-hour oral glucose tolerance test (OGTT) results, and random plasma glucose levels. In some embodiments, the diabetes is type 2 diabetes. In some embodiments, the diabetes is type 1 diabetes. In some embodiments, the HbA1c level is reduced by more than 0.25%. In some embodiments, the HbA1c level is reduced by more than 0.5%. In some embodiments, the HbA1c level is reduced by more than 0.75%. In some embodiments, the HbA1c level is reduced by more than 1.0%. In some embodiments, the HbA1c level is reduced by more than 1.5%. In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt is administered in combination with one or more hypoglycemic agents, such as biguanides, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, thiazolidinediones, meglitinides (glinides), alpha-glucosidase blockers, glucagon-like peptide-1 receptor agonists, insulin and insulin analogs. In some embodiments, the combination of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt and one or more hypoglycemic agents provides a therapeutic benefit that is greater than the additive effect of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt and the hypoglycemic agent when administered alone at the same dose.

[0015] In certain embodiments, a method for treating diabetes and sleep apnea comprises administering to a subject diagnosed with diabetes and sleep apnea (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount effective to reduce episodes of sleep apnea. DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description Provided herein are methods and compositions for use in treating diabetes, including type 1 diabetes, type 2 diabetes, and prediabetes. In embodiments, an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, alone or optionally in combination with one or more hypoglycemic agents, such as biguanides, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, thiazolidinediones, meglitinides (glinides), alpha-glucosidase blockers, glucagon-like peptide-1 receptor agonists, insulin, or insulin analogs, can be administered to reduce, prevent, slow the progression of, or delay the symptoms of metabolic disorders, such as type 1 diabetes, type 2 diabetes, prediabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, and / or postprandial hyperglycemia.

[0017] Disclosed herein are methods and compositions for use in treating diabetes, including type 1 diabetes, type 2 diabetes, and prediabetes, comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, for improving glycemic control. "Improved glycemic control," "improved glycemic control," or "glycemic control" refers to improved glucose tolerance, improved postprandial plasma glucose levels, improved fasting plasma glucose levels, improved HbA1c levels, or / and improved fasting plasma insulin levels.

[0018] The methods and compositions disclosed herein for use in treating diabetes or prediabetes, comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, improve, reduce, or alleviate symptoms or conditions associated with diabetes or prediabetes. Conditions associated with diabetes or prediabetes can include, for example, sleep apnea, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, nonalcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, and / or metabolic syndrome. The methods and compositions disclosed herein for use in treating diabetes or prediabetes, comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, can improve glycemic control, for example, lower fasting plasma glucose, lower postprandial plasma glucose, and / or lower HbA1c. The methods and compositions disclosed herein for use in treating diabetes or prediabetes, comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, can prevent, slow, delay, or reverse the progression of impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and insulin resistance resulting from metabolic syndrome to type 2 diabetes.

[0019] Disclosed herein are methods and compositions for use in treating diabetes or pre-diabetes comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, which may prevent, reduce the risk of, slow the progression of, delay or treat complications of diabetes or pre-diabetes, such as microvascular and macrovascular disease, including nephropathy, micro- or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive impairment, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot ulcers, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy, heart failure, arrhythmias, vascular restenosis, and / or stroke. The methods and compositions disclosed herein for use in the treatment of diabetes or prediabetes, comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, can prevent, slow the progression of, delay, or treat type 2 diabetes that exhibits primary or secondary failure to conventional (oral) hypoglycemic drug therapy alone or in combination. The methods and compositions disclosed herein for use in the treatment of diabetes or prediabetes, comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, can reduce the dose of conventional hypoglycemic medication required for sufficient therapeutic effect, thereby reducing the risk of adverse effects associated with conventional hypoglycemic medication. Disclosed herein are methods and compositions for use in the treatment of diabetes or prediabetes comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, which may maintain and / or improve insulin sensitivity and / or treat or prevent hyperinsulinemia and / or insulin resistance.

[0020] In some embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes, comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, are used to treat inadequate or insufficient glycemic control in subjects with diabetes or prediabetes. Inadequate or insufficient glycemic control can be considered a condition in which a patient exhibits an HbA1c value of greater than 6.0%, for example, greater than 6.5%, greater than 7.0%, greater than 7.5%, greater than 8%, greater than 8.5%, greater than 9%, greater than 9.5%, greater than 10%, greater than 10.5%, greater than 11%, or any value between 6.0% and 11.0%. For example, patients with inadequate or insufficient glycemic control can include patients with an HbA1c value of 6.5-7.0%, 7.0-7.5%, 7.5-10%, or 7.5-11%. For example, an inadequately controlled patient may refer to a patient with poor glycemic control, including, but not limited to, a patient with an HbA1c level of 9% or greater.

[0021] In some embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes, comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, reduce HbA1c levels by more than 0.25%. In some embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes, comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, reduce HbA1c levels by more than 0.5%. In some embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes, comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, reduce HbA1c levels by more than 0.75%. In some embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes, comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, reduce HbA1c levels by more than 1.0%. In some embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes, comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, reduce HbA1c levels by more than 1.25%. In some embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes, comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, reduce HbA1c levels by more than 1.5%.

[0022] The structure of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid can be represented as follows: [ka]

[0023] In certain embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid can be provided as an acid addition salt, zwitterion hydrate, zwitterion anhydrate, hydrochloride or hydrobromide salt, or in the form of a zwitterion monohydrate. Acid addition salts include but are not limited to maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethane-disulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, pantothenic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid or theophylline acetic acid addition salt, and 8-halotheophylline, for example, 8-bromo-theophylline.In some embodiments, inorganic acid addition salts can be used, including but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid addition salts.

[0024] The pathogenesis of diabetes and prediabetes can begin with an inflammatory cascade. Autoimmunity in diabetes and prediabetes can be initiated at the molecular and cellular levels. For example, serum cytokine concentrations can be elevated. In some patients, autoimmunity eventually transitions to immune-mediated inflammation, primarily focused on the pancreas. The pancreas is infiltrated by immune cells, including innate immune cells (monocytes, dendritic cells, mast cells) and adaptive immune cells (T helper 1, Th1; T helper 17, Th17), B cells, and plasma cells. Neutrophils, although not normally present in the pancreas, can migrate from the blood to the pancreas. Cytokines and chemokines, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), and granulocyte-monocyte colony-stimulating factor (GM-CSF), can activate endothelial cells and attract immune cells into the pancreas.

[0025] Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature mammalian CNS. Outside the brain, GABA is produced by pancreatic β-cells, as well as T cells and macrophages, which express all components of the GABAergic system, including its receptors, transporters, and metabolic enzymes. GABA acts as a negative regulator of macrophage inflammatory cytokine production and T cell activation by blocking calcium signaling and NFκB activity.

[0026] Diverse types of mouse and human immune cells express various GABA receptors (GABA-Rs). See Tian et al., Sci Rep 11, 5402 (2021). https: / / doi.org / 10.1038 / s41598-021-84751-3. GABA is known to limit mouse T cell production of IL-21, IFNγ2-4, TNFα3, and IL-123, while promoting TGFβ and Treg responses. Ibid. Antigen-presenting cells (APCs), such as macrophages, also express GABA. A GABA or GABA receptors express GABA-R, and their activation inhibits their inflammatory activity. A -R agonists reduced the secretion of IL-6, IL-1β, IL-12, and / or TNFα from LPS-stimulated mouse macrophages. Id.

[0027] Pancreatic beta cells synthesize GABA from glutamate via glutamic acid decarboxylase (GAD). See Al-Kuraishy et al., Int J Prev Med. 2021 Feb 24;12:19. Potential roles of GABA in pancreatic islets include regulating hormone secretion, suppressing immune responses, improving beta cell survival, and converting alpha cells to beta cells. Ibid. Notably, autoantibodies to GAD are associated with the development of type 1 diabetes, which is characterized by a decrease in beta cell mass and eventual disappearance. Ibid. Glucagon-like peptide 1 (GLP-1) activates pancreatic GAD, increasing GABA concentrations in beta cells, which in turn increases insulin synthesis and secretion. Ibid. GABA preserves beta cell mass through both its receptors and prevents the progression of type 1 and type 2 diabetes through its immunomodulatory and anti-inflammatory effects. Ibid. GABA exerts trophic effects on beta cells through activation of the PI3K / Akt pathway. Ibid. GABA content in beta cells is depleted and secretion is disrupted in pancreatic islets from patients with type 1 and type 2 diabetes, suggesting that the loss of GABA as a synchronizing signal for hormone release may be relevant to the pathogenesis of diabetes. Menegaz et al., Nat Metab 1, 1110-1126 (2019) Abstract.

[0028] (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid is a γ-aminobutyric acid aminotransferase (GABA-AT) inhibitor. GABA-AT is a pyridoxal 5'-phosphate-dependent enzyme responsible for the degradation of the inhibitory neurotransmitter GABA. (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid has a higher binding affinity to GABA-AT compared to CPP-115 (K of 1 and CPP-115). Ivalues ​​were found to be 9.7 μM and 59 μM, respectively), (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid inactivates GABA-AT at a higher rate than CPP-115 (k values ​​for (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid and CPP-115 inact The values ​​are 3.32 minutes, respectively. -1 and 2.05 mm -1 See U.S. Patent No. 9,993,449. Overall, the efficiency constant (k inact / K I =342 mM -1 minutes -1 ) is the efficiency constant (k inact / K I =34.9 mM -1 minutes -1 ) is 9.8 times greater than CPP-115; therefore, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid is 9.8 times more efficient as a GABA-AT inactivator than CPP-115. Unlike vigabatrin, CPP-115 has been reported not to inactivate or inhibit off-target enzymes such as aspartate aminotransferase (Asp-AT) and alanine aminotransferase (Ala-AT), which may have contributed to its greater safety compared to vigabatrin. (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid exhibited IC values ​​of 1.25 and 1.5% for both Asp-AT and Ala-AT. 50 CPP-115 is a very weak reversible inhibitor of K I The value is 0.116 mM, and k inact The value is 0.097 minutes -1 (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid is a moderate OAT inactivator. I The value is 0.0033 mM, and k inact The value is 0.025 minutes -1(S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid is a potent OAT inactivator. inact / K I value (7.6 mM -1 minutes -1 ) CPP-115 k inact / K I value (0.84 mM -1 minutes -1 ), (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid is 9.0 times more efficient as an inactivator of OAT than CPP-115, which is consistent with its greater efficiency as a GABA-AT inactivator.

[0029] Without wishing to be bound by any particular theory, selective inhibition of GABA-AT by (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof increases GABA concentrations at sites where GABA is normally present. A Activation of α-R suppresses the damaging inflammatory activity of lymphocytes and macrophages in the pancreas, simultaneously reducing the production of inflammatory cytokines and thereby suppressing the disease process. Furthermore, decreased GABA levels and alterations in the GABAergic signaling system contribute to the pathogenesis of diabetes and prediabetes. Administration of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof increases GABA levels, resulting in increased insulin secretion, suppression of immune responses, improved beta cell survival, promotion of alpha cell to beta cell conversion in the pancreas, and modulation of the GABAergic signaling system, thereby treating and ameliorating the symptoms of type 1 diabetes, type 2 diabetes, and prediabetes.

[0030] In certain embodiments, the terms "effective amount" or "therapeutically effective amount" may be used interchangeably and refer to an amount of a compound, substance, composition, medicament, or other substance that is effective in achieving the reduction, elimination, or prevention of diabetes or prediabetes and minimizing the side effects typically associated with hypoglycemic agents or other GABA-AT inhibitors.

[0031] In certain embodiments, an "effective amount" herein can range from about 0.01 mg to about 750 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, administered one to four or more times per day. For example, a pharmaceutical composition containing an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof may contain from about 0.01 mg to about 0.1 mg, about 0.1 mg to about 1 mg, 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 100 mg, about 100 mg to about 150 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 100 mg to about 150 mg, about mg~95 mg, 95 mg~100 mg, 100 mg~105 mg, 105 mg~110 mg, 110 mg~115 mg, 115 mg~120 mg, 120 mg~125 mg, 125 mg~130 mg, 130 mg~135 mg, 135 mg~140 mg, approx. 140 mg ~ approx. 145 mg, approx. 145 mg ~ approx. 150, approx. 150 mg ~ approx. 155 mg, approx. 155 mg ~ approx. 160 mg, approx. 160 mg ~ approx. 165 mg, approx. mg ~ approx. 190 mg, approx. 190 mg ~ approx. 195 mg, approx. 195 mg ~ approx. 200 mg, approx. 200 mg ~ approx. 205 mg, approx. 205 mg ~ approx. 210 mg, approx. 210 mg ~ approx. 215 mg, approx. 215 mg ~ approx. 220 mg, approx. mg ~ approx. 245 mg, approx. 245 mg ~ approx. 250, approx. 250mg~255 mg, 255 mg~260 mg, 260 mg~265 mg, 265 mg~270 mg, 270 mg~275 mg, 275 mg~280 mg, 280 mg~285 mg, 285 mg~290 mg, 290 mg~295 mg, 295 mg~300 300 mg to 305 mg, 305 mg to 310 mg, 310 mg to 315 mg, 315 mg to 320 mg, 320 mg to 325 mg, 325 mg to 330 mg, 335 mg to 340 mg, 340 mg to 345 mg, 345 mg ~ approx. 350, approx. 350 mg ~ approx. 355 mg, approx. 355 mg ~ approx. 360 mg, approx. 360 mg ~ approx. 365 mg, approx. 365 mg ~ approx. 370 mg, approx. 370 mg ~ approx. 375 mg, approx. 375 mg ~ approx. 380 mg, approx. mg ~ 405 mg, 405 mg ~ 410 mg, 410 mg ~ 415 mg, 415 mg ~ 420 mg, 420 mg ~ 425 mg, 425 mg ~ 430 mg, 430 mg ~ 435 mg, 435 mg ~ 440 mg, 440 mg ~ 445 mg, 445 mg ~ approx. 450, approx. 450 mg ~ approx. 455 mg, approx. 455 The compound may contain from about 460 mg to about 465 mg, from about 465 mg to about 470 mg, from about 470 mg to about 475 mg, from about 475 mg to about 480 mg, from about 480 mg to about 485 mg, from about 485 mg to about 490 mg, from about 490 mg to about 495 mg, or from about 495 mg to about 500 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0032] In certain embodiments, the pharmaceutical composition comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in an amount of 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 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, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147mg、148 mg、149 mg、150 mg、151mg、152 mg、153 mg、154 mg、155 mg、156 mg、157 mg、158 mg、159 mg、160 mg、161 mg、162 mg、163 mg、164 mg、165 mg、166 mg、167 mg、168 mg、169 mg、170 mg、171 mg、172 mg、173 mg、174 mg、175 mg、176 mg、177 mg、178 mg、179 mg、180 mg、181 mg、182 mg、183 mg、184 mg、185 mg、186 mg、187 mg、188 mg、189 mg、190 mg、191 mg、192mg、193 mg、194 mg、195 mg、196 mg、197 mg、198 mg、199 mg、200 mg、201 mg、202 mg、203 mg、204 mg、205 mg、206 mg、207 mg、208 mg、209 mg、210 mg、211 mg、212 mg、213 mg、214 mg、215 mg、216 mg、217 mg、218 mg、219 mg、220 mg、221 mg、222 mg、223 mg、224 mg、225 mg、226 mg、227 mg、228 mg、229 mg、230 mg、231 mg、232 mg、233 mg、234 mg、235 mg、236 mg、237 mg、238 mg、239 mg、240 mg、241 mg、242 mg、243 mg、244 mg、245 mg、246 mg、247 mg、248 mg、249 mg、250 mg、251mg、252 mg、253 mg、254 mg、255 mg、256 mg、257 mg、258 mg、259 mg、260 mg、261 mg、262 mg、263 mg、264 mg、265 mg、266 mg、267 mg、268 mg、269 mg、270 mg、271 mg、272 mg、273 mg、274 mg、275 mg、276 mg、277 mg、278 mg、279 mg、280 mg、281 mg、282 mg、283 mg、284 mg、285 mg、286 mg、287 mg、288 mg、289 mg、290mg、291 mg、292mg、293 mg、294 mg、295 mg、296 mg、297 mg、298 mg、299 mg、300 mg、301 mg、302 mg、303 mg、304 mg、305 mg、306 mg、307 mg308 mg、309 mg、310 mg、311 mg、312 mg、313 mg、314 mg、315 mg、316 mg、317 mg、318 mg、319 mg、320 mg、321 mg、322 mg、323 mg、324 mg、325 mg、326 mg、327 mg、328 mg、329 mg、230 mg、331 mg、332 mg、333 mg、334 mg、335 mg、336 mg、337 mg、338 mg、339 mg、340 mg、241 mg、342 mg、343 mg、344 mg、345 mg、346 mg、347 mg、348 mg、349 mg、350 mg、351mg、352 mg、353 mg、354 mg、355 mg、356 mg、357 mg、358 mg、359 mg、360 mg、361 mg、362 mg、363 mg、364 mg、365 mg、366 mg、367 mg、368 mg、369 mg、370 mg、371 mg、372 mg、373 mg、374 mg、375 mg、376 mg、377 mg、378 mg、379 mg、380 mg、381 mg、382 mg、383 mg、384 mg、385 mg、386 mg、387 mg、388 mg、389 mg、390 mg、391 mg、392mg、393 mg、394 mg、395 mg、396 mg、397 mg、398 mg、399 mg、400 mg、401 mg、402 mg、403 mg、404 mg、405 mg、406 mg、407 mg、408 mg、409 mg、410 mg、411 mg、412 mg、413 mg、414 mg、415 mg、416 mg、417 mg、418 mg、419 mg、420 mg、421 mg、422 mg、423 mg、424 mg、425 mg、426 mg、427 mg、428 mg、429 mg、430 mg、431 mg、432 mg、433mg, 434 mg, 435 mg, 436 mg, 237 mg, 438 mg, 439 mg, 440 mg, 441 mg, 442 mg, 443 mg, 444 mg, 445 mg, 446 mg, 447 mg, 448 mg, 449 mg, 450 mg, 451 mg, 452 mg, 453 mg, 454 mg, 455 mg, 456 mg, 457 mg, 458 mg, 459 mg, 460 mg, 461 mg, 462 mg, 463 mg, 464 mg, 465 mg, 466 mg, 467 mg, 468 mg, 469 mg, 470 mg, 471 mg, 472 mg, 473 mg, 474 mg, 475 mg, 476 mg, 477 mg, 478 mg, 479 mg, 480 mg, 481 mg, 482 mg, 483 mg, 484 mg, 485 mg, 486 mg, 487 mg, 488 mg, 489 mg, 490 mg, 491 mg, 492 mg, 493 mg, 494 mg, 495 mg, 496 mg, 497 mg, 498 mg, 499 mg, or 500 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0033] In certain embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject at about 0.01 mg / day to about 750 mg / day. For example, in certain embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 0.01 mg / day, about 0.1 mg / day, about 0.5 mg / day, about 1 mg / day, about 5 mg / day, about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 60 mg / day, about 65 mg / day, about 70 mg / day, about 75 mg / day, about 80 mg / day, about 85 mg / day, about 90 mg / day, about 95 mg / day, about 100 mg / day, about 105 mg / day, about 110 mg / day, about 115 mg / day, about 120 mg / day, about 125 mg / day, about 130 mg / day, about 135 mg / day, about 140 mg / day, about 145 mg / day, about 150 mg / day, about 155 mg / day, about 160 mg / day, about 165 mg / day, about 170 mg / day, about 175 mg / day, about 180 mg / day, about 185 mg / day, about 190 mg / day, about 195 mg / day, about 200 mg / day, about 205 mg / day, about 210 mg / day, about 215 mg / day, about 220 mg / day, about 225 mg / day, about 230 mg / day, about 235 mg / day, about 240 mg / day, about 245 mg / day, about 250 mg / day, about 2 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, about 200 mg / day, about 205 mg / day, about 210 mg / day, about 215 mg / day, about 220 mg / day, about 225 mg / day, about 230 mg / day, about 235 mg / day, about 240 mg / day, about 245 mg / day, about 250 mg / day, about 255 mg / day, about 260 mg / day, about 265 mg / day, approx. 270 mg / day, approx. 275 mg / day, about 280 mg / day, about 285 mg / day, about 290 mg / day, about 295 mg / day, about 300 mg / day, about 305 mg / day, about 310 mg / day, about 315 mg / day, about 320 mg / day, about 325 mg / day, about 330 mg / day, about 335 mg / day, about 340 mg / day, about 345 mg / day, about 350 mg / day, about 355 mg / day, about 360 mg / day, about 365 mg / day, about 370 mg / day, about 375 mg / day, about 380 mg / day, about 385 mg / day, about 390 mg / day, about 395 mg / day, about 400 mg / day, about 405mg / day, about 410 mg / day, about 415 mg / day, about 420 mg / day, about 425 mg / day, about 430 mg / day, about 435 mg / day, about 440 mg / day, about 445 mg / day, about 450 mg / day, about 455 mg / day, about 460 mg / day, about 465 mg / day, about 470 mg / day, about 475 mg / day, approx. 480 mg / day, approx. 485 mg / day, approx. 490 mg / day, approx. 495 mg / day, approx. 500 mg / day, approx. 505 mg / day, approx. 510 mg / day, approx. 515 mg / day, approx. mg / day, approx. 550 mg / day, approx. 555 mg / day, approx. 560 mg / day, approx. 565 mg / day, approx. 570 mg / day, approx. 575 mg / day, approx. 580 mg / day, approx. 585 mg / day, approx. 590 mg / day, approx. 595 mg / day, approx. mg / day, about 630 mg / day, about 635 mg / day, about 640 mg / day, about 645 mg / day, about 650 mg / day, about 655 mg / day, about 660 mg / day, about 665 mg / day, about 670 mg / day, about 675 mg / day, about 680 mg / day, about 685 mg / day, about 690 mg / day, about 695 mg / day, about 700 mg / day, about 705 The dose may be administered in one, two, three, four or more divided doses, such as about 710 mg / day, about 715 mg / day, about 720 mg / day, about 725 mg / day, about 730 mg / day, about 735 mg / day, about 740 mg / day, about 745 mg / day, or about 750 mg / day. In certain embodiments, subjects may be started on a low dose, and the dose may be gradually increased over time.

[0034] In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject diagnosed with diabetes or prediabetes via a pharmaceutical composition. Pharmaceutical compositions herein include dosage forms. Dosage forms herein include unit doses. In some embodiments, various dosage forms, including conventional formulations and modified-release formulations, can be administered once, twice, three times, four times, or more times per day, as described below. In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject once or twice per day (e.g., morning and / or evening). In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject three times per day (e.g., morning, midday, and bedtime, or every 8 hours). In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject four times a day (for example, morning, noon, evening, and bedtime, or every 6 hours). In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject via continuous infusion. In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject at the onset of a diabetic or prediabetic symptom episode, regardless of when it occurs. Any suitable administration route can be used, for example, oral, rectal, nasal, pulmonary, vaginal, sublingual, transdermal, intravenous, intraarterial, epidural, intramuscular, intraperitoneal, and subcutaneous. Suitable dosage forms include tablets, capsules, oral liquids, powders, aerosols, topical liquids, patches, transdermal modalities such as creams and ointments, parenteral formulations, and suppositories. In certain embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is used to prepare a medicament for the treatment of diabetes or prediabetes.

[0035] In one embodiment, a method for treating diabetes or prediabetes is provided, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition improves the symptoms of diabetes or prediabetes for more than 1 hour after administration to the subject.In one embodiment, a method for treating diabetes or prediabetes is provided, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition improves the symptoms of diabetes or prediabetes for more than 2 hours after administration to the subject. In one embodiment, a method for treating diabetes or prediabetes is provided, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition improves the symptoms of diabetes or prediabetes for more than 3 hours after administration to the subject.In one embodiment, a method for treating diabetes or prediabetes is provided, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition improves the symptoms of diabetes or prediabetes for more than 4 hours after administration to the subject. In certain embodiments, a method for treating diabetes or prediabetes is provided, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition results in improvement of symptoms of diabetes or prediabetes for more than 6 hours after administration to the subject.In some embodiments, provided herein is a method for treating diabetes or prediabetes, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, wherein the composition improves the symptoms of diabetes or prediabetes for more than 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration to the subject.In some embodiments, the pharmaceutical composition improves the next-day function of the subject diagnosed with diabetes or prediabetes.For example, the pharmaceutical composition can improve the symptoms of diabetes or prediabetes for more than about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours or about 24 hours after administration and waking up from a night's sleep.

[0036] In some embodiments, as described above, the pharmaceutical compositions herein can be provided with a conventional release profile or a modified release profile. Pharmaceutical compositions can be prepared using a pharmaceutically acceptable "carrier" made of a material that is considered safe and effective. "Carrier" includes all ingredients present in a pharmaceutical formulation other than the active ingredient. The term "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers and coating compositions. Those skilled in the art are familiar with such pharmaceutical carriers and methods for formulating pharmaceutical compositions using such carriers.

[0037] In some embodiments, the pharmaceutical composition herein is a modified release dosage form that provides a modified release profile. The modified release profile can be an immediate release, delayed release, or sustained release profile. Conventional (or non-modified) release oral dosage forms, such as tablets, capsules, suppositories, syrups, solutions, and suspensions, generally release drugs into the oral cavity, stomach, or intestines when the tablet, capsule shell, or suppository dissolves, or in the case of syrups, solutions, and suspensions, they are swallowed. The drug release pattern from modified release (MR) dosage forms is intentionally changed from that of conventional dosage forms to achieve desired therapeutic goals and / or better patient compliance. MR pharmaceuticals include orally disintegrating dosage forms (ODDFs) that provide immediate release, sustained release dosage forms, delayed release dosage forms (e.g., enteric-coated), and pulsed release dosage forms.

[0038] ODDFs are solid dosage forms containing pharmaceutical substances or active ingredients that rapidly disintegrate upon placement on the tongue, usually within a few seconds. ODDF disintegration times generally range from one or two seconds to approximately one minute. ODDFs are designed to rapidly disintegrate or dissolve upon contact with saliva. This administration method can be beneficial for people who may have difficulty swallowing tablets, whether due to physical weakness or psychological reasons. Subjects with diabetes or prediabetes may exhibit such behavior. ODDFs can rapidly deliver drugs to the bloodstream via mucous membranes, resulting in a rapid onset of action. Examples of ODDFs include orally disintegrating tablets, capsules, and rapidly dissolving films and wafers.

[0039] An extended-release dosage form (ERDF) has a sustained-release profile, allowing for reduced dosing frequency compared to that exhibited by conventional dosage forms, such as solutions or non-modified-release dosage forms. ERDFs provide a sustained duration of drug action. Suitable formulations providing extended-release profiles are well known in the art. For example, coated extended-release beads or granules ("beads" and "granules" are used interchangeably herein) are well known in the art, in which (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is loaded onto beads, e.g., nonpareil confectionery beads, and then coated with a conventional release-retarding material, such as wax or an enteric coating. In an embodiment, the beads can be formed by mixing (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof with a material to provide a mass from which the drug can be leached. In some embodiments, beads can be designed to provide different release rates by varying coating or bulk properties, such as thickness, porosity, the use of different materials, etc. Beads with different release rates can be combined into a single dosage form to provide variable or sustained release. The beads can be placed in capsules or compressed into tablets.

[0040] In some embodiments, the modified dosage form herein incorporates a delayed-release dosage form with a delayed-release profile. The delayed-release dosage form can include delayed-release tablets or delayed-release capsules. A delayed-release tablet is a solid dosage form that releases a drug (or drugs), such as (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, at a time other than immediately after administration. A delayed-release capsule is a solid dosage form in which a drug is enclosed in a hard or soft soluble container made of a suitable form of gelatin, and the drug is released at a time other than immediately after administration. For example, enteric-coated tablets, capsules, particles, and beads are well-known examples of delayed-release dosage forms. Enteric-coated tablets, capsules, particles, and beads pass through the stomach and release the drug in the intestine. In some embodiments, the delayed-release tablet is a solid dosage form containing a collection of pharmaceutical particles that releases a drug (or drugs) at a time other than immediately after administration. In some embodiments, the collection of pharmaceutical particles is covered with a coating that delays the release of the drug. In some embodiments, a delayed-release capsule is a solid dosage form containing a collection of pharmaceutical particles that releases a drug (or drugs) at a time other than immediately after administration. In some embodiments, the collection of pharmaceutical particles is covered with a coating that delays the release of the drug.

[0041] Delayed-release dosage forms are well known to those skilled in the art. For example, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt is loaded onto beads, such as nonpareil confectionery beads, and then coated with conventional release-delaying materials, such as wax, enteric coating, etc., to form delayed-release beads or granules. In some embodiments, beads can be formed by mixing (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt with materials to provide a mass from which the drug is leached. In some embodiments, beads can be designed to provide different release rates by varying the properties of the coating or mass, such as thickness, porosity, the use of different materials, etc. In some embodiments, the enteric-coated granules of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salts can be contained in an enteric-coated capsule or tablet that releases the granules in the small intestine. In some embodiments, the granules have a coating that keeps the coated granules intact until they reach at least the ileum, and then provides delayed release of the drug in the colon. Suitable enteric coating materials, such as Eudragit® coatings, such as methacrylic acid and methyl methacrylate polymers, are well known in the art. The granules can be placed in capsules or compressed into tablets.

[0042] In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is incorporated into a porous inert carrier to provide a delayed-release profile. In some embodiments, the porous inert carrier incorporates channels or passageways through which the drug diffuses into the surrounding fluid. In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is incorporated into an ion exchange resin to provide a delayed-release profile. The delayed effect may be due to a predetermined release rate of the drug from the resin when the drug-resin complex contacts gastrointestinal fluid and the ionic components dissolved therein. In some embodiments, a membrane is utilized to control the release rate from the drug-containing reservoir. In some embodiments, liquid formulations may also be utilized to provide a delayed-release profile. For example, liquid formulations comprise solid particles dispersed throughout a liquid phase in which the particles do not dissolve. The suspensions of the present invention are formulated to allow for at least reduced dosing frequency compared to drugs presented in conventional dosage forms (e.g., as solutions or conventional solid dosage forms that rapidly release the drug), e.g., suspensions of ion exchange resin components or microbeads.

[0043] In some embodiments, the pharmaceutical compositions described herein are suitable for parenteral administration, including, for example, intramuscular (im), intravenous (iv), subcutaneous (sc), intraperitoneal (ip), epidural, or intrathecal (it) administration. Parenteral compositions should be sterile for administration by injection, infusion, or implantation into the body and may be packaged in either single-dose or multi-dose containers. In some embodiments, a liquid pharmaceutical composition for parenteral administration to a subject contains an active substance, such as (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, in any of the amounts described above. In some embodiments, the pharmaceutical composition for parenteral administration is formulated, for example, in a total volume of about 10 ml, about 20 ml, about 25 ml, about 50 ml, about 100 ml, about 200 ml, about 250 ml, or about 500 ml. In some embodiments, the composition is contained in a bag, glass vial, plastic vial, or bottle.

[0044] The pharmaceutical compositions for parenteral administration provided herein may contain one or more additives, such as solvents, solubility enhancers, suspending agents, buffers, isotonicity agents, stabilizers, or antimicrobial preservatives.When used, the additives of the parenteral composition do not adversely affect the stability, bioavailability, safety, and / or efficacy of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salts used in the composition.Therefore, a parenteral composition is provided in which there is no incompatibility between any of the components of the dosage form.

[0045] In some embodiments, the parenteral composition (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt comprises a stabilizing amount of at least one additive.For example, the additive can be selected from the group consisting of buffering agents, solubilizing agents, isotonicity agents, antioxidants, chelating agents, antibacterial agents and preservatives.Those skilled in the art will understand that additives can have one or more functions and can be classified into one or more defined groups.

[0046] In some embodiments, in the parenteral composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof and an additive, the additive is present in a weight percent (w / v) of, for example, less than about 10%, less than about 5%, less than about 2.5%, less than about 1%, or less than about 0.5%. In some embodiments, the additive is present in a weight percent of, for example, about 1.0% to about 10%, about 10% to about 25%, about 15% to about 35%, about 0.5% to about 5%, about 0.001% to about 1%, about 0.01% to about 1%, about 0.1% to about 1%, or about 0.5% to about 1%. In some embodiments, the additive is present in a weight percentage of, for example, about 0.001% to about 1%, about 0.01% to about 1%, about 1.0% to about 5%, about 10% to about 15%, or about 1% to about 15%.

[0047] In some embodiments, a parenteral composition of an active substance, such as (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, is provided, wherein the pH of the composition is about 4.0 to about 8.0. In some embodiments, the pH of the composition is, for example, about 5.0 to about 8.0, about 6.0 to about 8.0, or about 6.5 to about 8.0. In some embodiments, the pH of the composition is, for example, about 6.5 to about 7.5, about 7.0 to about 7.8, about 7.2 to about 7.8, or about 7.3 to about 7.6. In some embodiments, the pH of the aqueous solution is, for example, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.7, about 7.8, about 8.0, about 8.2, about 8.4, or about 8.6.

[0048] It is understood that the dosage of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt provided herein is applicable to all dosage forms described herein, including conventional dosage forms, modified dosage forms, and parenteral formulations described herein. Those skilled in the art will determine the appropriate amount depending on criteria such as dosage form, route of administration, subject tolerance, efficacy, therapeutic goals, and therapeutic effect, among other pharmaceutically acceptable criteria.

[0049] The clinical effectiveness of treatment can be monitored by any method known in the art.The measurable parameters for monitoring effectiveness depend on the condition being treated.Both subjective parameters (e.g., patient report) and objective parameters (e.g., fasting blood glucose level, HbA1c, 2-hour oral glucose tolerance test (OGTT) result, and random plasma glucose level) can be used to monitor the condition or improvement of diabetes or prediabetes.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0051] As used herein, the term "about" or "approximately" refers to within an acceptable error range of a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 standard deviations or more than 3 standard deviations, in accordance with the practice in the art. Alternatively, "about" can refer to a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value.

[0052] "Amelioration" refers to the treatment of diabetes or prediabetes, including all symptoms normally associated with diabetes or prediabetes.

[0053] "Improved next day function" or "has improved next day function" refers to an improvement after awakening from a night's sleep period, where the beneficial effects of administration of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof apply to diabetic or pre-diabetic symptoms and is discernible subjectively by the subject or objectively by an observer for a period of time after awakening, such as 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, etc.

[0054] "Treating," "treatment," or "treat" can refer to reducing, ameliorating, alleviating, ameliorating, relieving, suppressing, reversing, and / or alleviating the symptoms of diabetes or prediabetes in a subject, or delaying (preventing) the onset of symptoms of diabetes or prediabetes in a subject. In certain embodiments, "treating," "treat," or "treatment" can refer to preventing the onset of clinical symptoms of a disease or condition in a subject who may be suffering from or predisposed to the disease or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the disease or condition. "Treating," "treat," or "treatment" also refers to suppressing or alleviating diabetes or prediabetes, for example, causing regression of diabetes or prediabetes or at least one of its clinical or subclinical symptoms. The benefit to a treated subject may be statistically significant, mathematically significant, or at least perceptible to the subject and / or physician. Nevertheless, preventative (prophylactic) treatment and therapeutic (curative) treatment are two separate embodiments of the present disclosure.

[0055] "Pharmaceutically acceptable" refers to molecular entities and compositions that are "generally regarded as safe," e.g., physiologically tolerated, and generally do not produce allergic or similar undesirable reactions, such as stomach upset, when administered to humans. In certain embodiments, the term refers to molecular entities and compositions that have been approved by a federal or state regulatory agency as a GRAS listed under Sections 204(s) and 409 of the Federal Food, Drug, and Cosmetic Act, and are subject to premarket review and approval by the FDA or similar listing, the United States Pharmacopoeia, or other generally recognized pharmacopeia for use in animals, more particularly in humans.

[0056] "Administered simultaneously," "administered in combination," "combination of," or "administered together" can be used interchangeably and can mean that two or more agents are administered during the course of treatment. The agents can be administered simultaneously or separately at intervals. The agents can be administered in a single dosage form or in separate dosage forms.

[0057] A "subject in need thereof" includes an individual diagnosed with diabetes or prediabetes. An individual includes a mammal. Methods and compositions comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof can be provided to any individual, including, for example, when the subject is a newborn, infant, pediatric subject (6 months to 12 years), adolescent subject (12 to 18 years), or adult (18 years or older). A subject includes a mammal. "Patient" and "subject" are used interchangeably herein.

[0058] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of compounds defined herein, which are modified by making acid or base salts of the parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid. Pharmaceutically acceptable salts can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods.

[0059] It is understood that the examples and embodiments provided herein are illustrative examples and working embodiments. Those skilled in the art will envision various modifications of the examples and embodiments that are consistent with the scope of the disclosure of this specification. Such modifications are intended to be encompassed by the scope of the claims.

Claims

1. A method for treating diabetes, comprising administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

2. 2. The method of treating diabetes according to claim 1, wherein the diabetes is type 2 diabetes.

3. 2. The method of treating diabetes according to claim 1, wherein the diabetes is type 1 diabetes.

4. 2. The method of treating diabetes according to claim 1, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount effective to reduce one or more of HbA1c levels, fasting plasma glucose, a 2-hour oral glucose tolerance test (OGTT) result, and random plasma glucose levels.

5. 5. The method of treating diabetes according to claim 4, wherein HbA1c levels are reduced by more than 0.5%.

6. 5. The method of treating diabetes according to claim 4, wherein HbA1c levels are reduced by more than 1.0%.

7. 10. The method of treating diabetes according to claim 1, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 0.01 mg to about 750 mg.

8. 2. The method of treating diabetes according to claim 1, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in combination with one or more hypoglycemic agents selected from the group consisting of biguanides, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, glucagon-like peptide-1 receptor agonists, insulin, and insulin analogs.

9. A method for treating prediabetes, comprising administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

10. 10. The method of treating prediabetes according to claim 9, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount effective to reduce one or more of HbA1c levels, fasting plasma glucose, a 2-hour oral glucose tolerance test (OGTT) result, and random plasma glucose levels.

11. 11. The method of treating prediabetes of claim 10, wherein HbA1c levels are reduced by more than 0.5%.

12. 11. The method of treating prediabetes of claim 10, wherein HbA1c levels are reduced by more than 1.0%.

13. 10. The method of treating prediabetes according to claim 9, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 0.01 mg to about 750 mg.

14. 10. The method of treating prediabetes according to claim 9, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in combination with one or more hypoglycemic agents selected from the group consisting of biguanides, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, glucagon-like peptide-1 receptor agonists, insulin, and insulin analogs.

15. A method for treating diabetes and sleep apnea, comprising administering to a subject diagnosed with diabetes and sleep apnea (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount effective to reduce episodes of sleep apnea.

16. 16. The method of treating diabetes and sleep apnea according to claim 15, wherein the diabetic disease is type 2 diabetes.

17. 16. The method of treating diabetes and sleep apnea according to claim 15, wherein the diabetes is type 1 diabetes.

18. 16. The method of treating diabetes and sleep apnea according to claim 15, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 0.01 mg to about 750 mg.

19. 16. The method of treating diabetes and sleep apnea according to claim 15, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in combination with one or more hypoglycemic agents selected from the group consisting of biguanides, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, glucagon-like peptide-1 receptor agonists, insulin, and insulin analogs.

20. 16. The method of treating diabetes and sleep apnea of ​​claim 15, wherein administration is effective to reduce one or more of HbA1c levels, fasting plasma glucose, 2-hour oral glucose tolerance test (OGTT) results, and random plasma glucose levels in the subject.

21. 21. The method of treating diabetes and sleep apnea of ​​claim 20, wherein HbA1c levels are reduced by more than 0.5%.

22. 21. The method of treating diabetes and sleep apnea of ​​claim 20, wherein HbA1c levels are reduced by more than 1%.

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