amg-837 and Diabetes-Mellitus--Type-2

GPR40 belongs to the GPCR family and the activation of GPR40 has been shown to induce glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells as well as incretin secretion from intestinal endocrine cells. Therefore, GPR40 has emerged as a viable and promising therapeutic target for type 2 diabetes mellitus (T2DM) without the risk of hypoglycemia. However, the termination of TAK-875 in phase III clinical trials for the hepatotoxicity issue threw doubt over the long-term safety of targeting GPR40. Herein, we summarized the newly disclosed biological characteristics and the druglikeness-based structural evolution of GPR40 agonists to advance the development of GPR40-based anti-diabetic drugs.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Drug Discovery; Humans; Hypoglycemic Agents; Models, Molecular; Molecular Targeted Therapy; Receptors, G-Protein-Coupled; Sulfones

Apart from functioning as an energy source and important structural components of biological membranes, Free Fatty acids (FFAs) play a key role in the regulation of metabolic homeostasis. FFAs activate specific G-protein coupled receptors (GPCRs) in pancreatic β-cells, immune cells adipose, and intestine. GPR40 (also known as FFA receptor 1) is primarily expressed in pancreatic .-cells and is activated by medium-chain and long-chain FFAs. GPR40 has been shown to augment glucose dependent insulin secretion (GDIS) from pancreatic .-cells and is widely studied drug discovery target for the treatment of type 2 diabetes mellitus (T2DM) and other metabolic diseases. Several synthetic agonists of GPR40 augment insulin secretion from pancreatic β- cells and consequently improve glucose tolerance and restore metabolic homeostasis in various rodent models of T2DM. GPR40 agonists TAK-875 and AMG 837 have reached clinical trials and TAK 875 was shown to improve glycemic control in Type 2 diabetic patients. However, phase III clinical trials involving TAK-875 were recently terminated due to signs of liver toxicity in patients. Despite this setback, therapies based on GPR40 agonism provide an attractive alternative in the discovery of new anti-diabetic drugs. This review summarizes our current understanding of the physiological functions of GPR40, benefits and future prospects of GPR40 agonists to treat patients with T2DM.

Topics: Animals; Benzofurans; Biphenyl Compounds; Diabetes Mellitus, Type 2; Drug Design; Fatty Acids, Nonesterified; Humans; Hypoglycemic Agents; Insulin; Receptors, G-Protein-Coupled; Sulfones

The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptors (PPARs) have attracted interest as potent targets for the treatment of metabolic syndrome such as type 2 diabetes. Based on the hypothesis that the dual agonists of PPARs and FFA1 would act as insulin sensitizers and secretagogues by simultaneous activation of PPARs and FFA1, we developed the design strategy to obtain dual PPARs/FFA1 agonist by hybrid FFA1 agonist 1 with PPARδ agonist 2 in consideration of their structural similarity. As expected, systematic exploration of structure-activity relationship and molecular modeling, results in the discovery of lead compound 15, a pan agonist with relative balanced activities between FFA1, PPARγ and PPARδ. The dose-response relationship studies suggested that the pan agonist 15 suppressed the excursion of blood glucose levels in a dose-dependent manner. During a 5-days treatment in ob/ob mice, the pan agonist 15 (100 mg/kg) revealed sustained hypoglycemic effect, even proximity to the most advanced FFA1 agonist (TAK-875, 40 mg/kg), which might be attributed to its pan PPARs/FFA1 activities to simultaneous regulate the mechanism of insulin secretion and resistance. These positive results suggest that the dual PPARs/FFA1 agonists such as lead compound 15 might be novel therapeutic strategy to modulate the complex pathological mechanisms of type 2 diabetes.

Topics: Animals; CHO Cells; Cricetulus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Design; Glucose Tolerance Test; HEK293 Cells; Hep G2 Cells; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred ICR; Mice, Obese; Models, Molecular; Molecular Structure; PPAR delta; PPAR gamma; Receptors, G-Protein-Coupled; Structure-Activity Relationship

The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet β-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Discovery; Glucose Tolerance Test; HEK293 Cells; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Structure; Piperidines; Rats; Rats, Zucker; Receptors, G-Protein-Coupled; Spiro Compounds; Structure-Activity Relationship

With growing needs for new antidiabetic drugs which are safe and effective alone or in combination with existing drugs, G-protein coupled receptor 40 (GPR40) has drawn a considerable attention as a potential therapeutic target for type 2 diabetes. As GPR40 agonist may offer advantages to commonly used agents, by acting ambient glucose dependent manner which mechanistically leads to reduced risk of developing hypoglycemia. Since deorphanization in 2003, development of small molecule GPR40 agonists has been spurred by several research groups. There are a number of lead molecules targeting GPR40, and among these molecules TAK-875 (full agonist) and AMG 837 (partial agonist) advanced into clinical stage.

Topics: Benzofurans; Biphenyl Compounds; Diabetes Mellitus, Type 2; Drug Discovery; Drugs, Investigational; Humans; Hypoglycemic Agents; Receptors, G-Protein-Coupled; Signal Transduction; Sulfones

The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and is recognized as an interesting new target for treatment of type 2 diabetes. Several series of selective FFA1 agonists are already known. Most of these are derived from free fatty acids (FFAs) or glitazones and are relatively lipophilic. Aiming for the development of potent, selective, and less lipophilic FFA1 agonists, the terminal phenyl of a known compound series was replaced by nitrogen containing heterocycles. This resulted in the identification of 37, a selective FFA1 agonist with potent activity on recombinant human FFA1 receptors and on the rat insulinoma cell line INS-1E, optimal lipophilicity, and excellent in vitro permeability and metabolic stability.

Topics: Animals; Cell Line, Tumor; Cell Membrane Permeability; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; In Vitro Techniques; Insulin; Insulin Secretion; Microsomes, Liver; Models, Molecular; Phenylpropionates; Pyridines; Rats; Receptors, G-Protein-Coupled; Recombinant Proteins; Structure-Activity Relationship