tak-875 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

To assess the efficacy and safety of fasiglifam 25 and 50 mg in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise.. This phase III, double-blind, placebo-controlled, multicentre study included 192 patients randomized to once-daily treatment with fasiglifam 25 mg (n = 63) or 50 mg (n = 62) or placebo (n = 67) for 24 weeks. The primary efficacy endpoint was the change from baseline in glycated haemoglobin (HbA1c) at week 24.. At week 24, both fasiglifam groups had significantly reduced HbA1c levels compared with the placebo group (p < 0.0001). The least squares mean change from baseline in HbA1c was 0.16% with placebo, -0.57% with fasiglifam 25 mg and -0.83% with fasiglifam 50 mg. The percentage of patients who achieved an HbA1c target of <6.9% at week 24 was also significantly higher (p < 0.05) for fasiglifam 25 mg (30.2%) and 50 mg (54.8%) compared with placebo (13.8%). Fasiglifam significantly reduced fasting plasma glucose levels at all assessment points, starting from week 2. The incidence and types of treatment-emergent adverse events in each fasiglifam group were similar to those in the placebo group, and hypoglycaemia was reported in 1 patient receiving fasiglifam 50 mg. There were no clinically meaningful changes in body weight in any treatment group.. Fasiglifam significantly improved glycaemic control and was well tolerated, with a low risk of hypoglycaemia in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise; however, in a recent review of data from overall fasiglifam global clinical trials, concerns about liver safety arose and the clinical development of fasiglifam was terminated after this trial was completed.

Topics: Aged; Asian People; Benzofurans; Blood Glucose; Diabetes Mellitus, Type 2; Diet, Diabetic; Double-Blind Method; Exercise; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Japan; Male; Middle Aged; Receptors, G-Protein-Coupled; Sulfones

Free fatty acid receptor 1 (FFA1 or GPR40) has been studied for many years as a target for the treatment of type 2 diabetes mellitus. In order to increase potency and reduce hepatotoxicity, a series of novel compounds containing imidazo[1,2-a]pyridine scaffold as GPR40 agonist were synthesized. Compound I-14 was identified as an effective agonist as shown by the conspicuous drop in blood glucose in normal and diabetic mice. It had no risk of hepatotoxicity compared with TAK-875. Moreover, good pharmacokinetic (PK) properties of I-14 were observed (CL = 27.26 ml/h/kg, t

Topics: Animals; Benzofurans; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Phenylpropionates; Pyridines; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Sulfones

The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPARδ agonists would increase insulin secretion and sensibility by FFA1 and PPARδ activation. In this study, we hybrid FFA1 agonist AM-4668 with PPARδ agonist GW501516, leading to the identification of orally bioavailable dual agonist 32, which revealed high selectivity over other PPARs. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPARδ agonist could be a valuable therapy for type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Discovery; Glucose Tolerance Test; Hypoglycemic Agents; Mice; PPAR delta; Receptors, G-Protein-Coupled; Thiazoles

Based on an old phenoxyacetic acid scaffold, CPU014 (compound 14) has been identified as a superior agonist by comprehensive exploration of structure-activity relationship. In vitro toxicity study suggested that CPU014 has lower risk of hepatotoxicity than TAK-875. During acute toxicity study (5-500 mg/kg), a favorable therapeutic window of CPU014 was observed by evaluation of plasma profiles and liver slices. Moreover, CPU014 promotes insulin secretion in a glucose-dependent manner, while no GLP-1 secretion has been enhanced. Other than good pharmacokinetic properties, CPU014 significantly improved glucose tolerance both in normal and diabetic models without the risk of hypoglycemia. These subversive findings provided a safer candidate CPU014, which is currently in preclinical study to assess its potential for the treatment of diabetes.

Topics: Acetates; Animals; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Design; Glucose Tolerance Test; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Molecular Structure; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Structure-Activity Relationship

GPR40, also known as free fatty acid receptor 1 (FFAR1), is a member of G protein-coupled receptors (GPCR) family and has emerged as an attractive target for the treatment of type 2 diabetes mellitus. So far, most of the synthetic GPR40 agonists, including several drug candidates discontinued in clinical trials, were derived from the phenylpropionic acid scaffold. For discovering novel GPR40 agonists with diverse chemical structures, a series of phenylpropiolic acid derivatives were designed, synthesized, and evaluated under a battery of bioassays. Compound 9, the most potent compound in this series, exhibited submicromolar agonist activity and similar agonistic efficacy compared to that of TAK-875. In addition, compound 9 was able to dose-dependently amplify glucose-stimulated insulin secretion (GSIS) in pancreatic β-cell line MIN6, which could be reversed by a selective GPR40 antagonist GW1100. In addition, compound 9 was found to have potent glucose-lowering effects during an oral glucose tolerance test in normal C57BL/6 mice.

Topics: Animals; Cell Line; Diabetes Mellitus, Type 2; Drug Design; Glucose; Glucose Tolerance Test; HEK293 Cells; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Mice, Inbred C57BL; Phenylpropionates; Receptors, G-Protein-Coupled

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

Topics: Administration, Oral; Animals; Benzofurans; Blood Glucose; Cell Line; CHO Cells; Cricetulus; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Male; Mice, Inbred ICR; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Sulfones; Thiophenes

The free fatty acid receptor 1 (FFA1/GPR40) has attracted extensive attention as a novel antidiabetic target. Aiming to explore the chemical space of FFA1 agonists, a new series of lead compounds with amide linker were designed and synthesized by combining the scaffolds of NIH screened lead compound 1 and GW9508. Among them, the optimal lead compound 17 exhibited a considerable agonistic activity (45.78%) compared to the NIH screened compound 1 (15.32%). During OGTT in normal mice, the compound 17 revealed a significant glucose-lowering effect (-23.7%) at the dose of 50mg/kg, proximity to the hypoglycemic effect (-27.8%) of Metformin (200mg/kg). In addition, the compound 17 (100mg/kg) also exhibited a significant improvement in glucose tolerance with a 29.1% reduction of glucose AUC

Topics: Amides; Animals; Area Under Curve; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose Tolerance Test; Mice; Structure-Activity Relationship

The free fatty acid receptor 1 (FFA1/GPR40) has attracted interest as a novel target for the treatment of type 2 diabetes. Several series of FFA1 agonists including TAK-875, the most advanced compound terminated in phase III studies due to concerns about liver toxicity, have been hampered by relatively high molecular weight and lipophilicity. Aiming to develop potent FFA1 agonists with low risk of liver toxicity by decreasing the lipophilicity, the middle phenyl of TAK-875 was replaced by 11 polar five-membered heteroaromatics. Subsequently, systematic exploration of SAR and application of molecular modeling, leads to the identification of compound 44, which was an excellent FFA1 agonist with robustly hypoglycemic effect both in normal and type 2 diabetic mice, low risks of hypoglycemia and liver toxicity even at the twice molar dose of TAK-875. Meanwhile, two important findings were noted. First, the methyl group in our thiazole series occupied a small hydrophobic subpocket which had no interactions with TAK-875. Furthermore, the agonistic activity revealed a good correlation with the dihedral angle between thiazole core and the terminal benzene ring. These results promote the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.

Topics: Animals; Blood Glucose; CHO Cells; Cricetulus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Design; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Models, Molecular; Molecular Structure; Receptors, G-Protein-Coupled; Structure-Activity Relationship; Thiazoles

The free fatty acid receptor 1 (FFA1) has gained significant interest as a novel antidiabetic target. Most of FFA1 agonists reported in the literature bearing a common biphenyl scaffold, which was crucial for toxicity verified by the researchers of Daiichi Sankyo. Herein, we describe the systematic exploration of non-biphenyl scaffold and further chemical modification of the optimal pyrrole scaffold. All of these efforts led to the identification of compound 11 as a potent and orally bioavailable FFA1 agonist without the risk of hypoglycemia. Further molecular modeling studies promoted the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.

Topics: Administration, Oral; Animals; Biological Availability; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Discovery; Glucose Tolerance Test; Male; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Pyrroles; Receptors, G-Protein-Coupled; Structure-Activity Relationship

Topics: Animals; Blood Glucose; Click Chemistry; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Discovery; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Models, Molecular; Molecular Structure; Receptors, G-Protein-Coupled; Structure-Activity Relationship; Triazoles

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

Free fatty acid receptor 1 (FFA1) is a new potential drug target for the treatment of type 2 diabetes because of its role in amplifying glucose-stimulated insulin secretion in pancreatic β-cell. In the present studies, we identified phenoxyacetic acid derivative (18b) as a potent FFA1 agonist (EC50=62.3 nM) based on the structure of phenylpropanoic acid derivative 4p. Moreover, compound 18b could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice without observation of hypoglycemic side effect. Additionally, compound 18b exhibited acceptable PK profiles. In summary, compound 18b with ideal PK profiles exhibited good activity in vitro and in vivo, and might be a promising drug candidate for the treatment of diabetes mellitus.

Topics: Acetates; Animals; Diabetes Mellitus, Type 2; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Models, Molecular; Rats; Receptors, G-Protein-Coupled; Structure-Activity Relationship

The free fatty acid receptor 1 (FFA1) has attracted extensive attention as a novel antidiabetic target in the last decade. Several FFA1 agonists reported in the literature have been suffered from relatively high molecular weight and lipophilicity. We have previously reported the FFA1 agonist 1. Based on the common amide structural characteristic of SAR1 and NIH screened compound, we here describe the continued structure-activity exploration to decrease the molecular weight and lipophilicity of the compound 1 series by converting various amide linkers. All of these efforts lead to the discovery of the preferable lead compound 18, a compound with considerable agonistic activity, high LE and LLE values, lower lipophilicity than previously reported agonists, and appreciable efficacy on glucose tolerance in both normal and type 2 diabetic mice.

Topics: Acetanilides; Animals; CHO Cells; Cricetulus; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Design; Humans; Male; Mice, Inbred C57BL; Mice, Inbred ICR; Molecular Structure; Receptors, G-Protein-Coupled; Structure-Activity Relationship

The free fatty acid receptor 1 (FFA1) is a novel antidiabetic target for the treatment of type 2 diabetes based on particular mechanism in amplifying glucose-stimulated insulin secretion. We have previously identified a series of phenoxyacetic acid derivatives. Herein, we describe the further chemical modification of this series directed by ligand efficiency and ligand lipophilicity efficiency. All of these efforts lead to the discovery of the promising candidate 16, an excellent FFA1 agonist with robust agonistic activity (43.6 nM), desired LE and LLE values. Moreover, compound 16 revealed a great potential for improving the hyperglycemia levels in both normal and type 2 diabetic mice without the risk of hypoglycemia even at the high dose of 40 mg/kg.

Topics: Acetates; Animals; Binding Sites; Calcium; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus, Type 2; Drug Design; Glucose Tolerance Test; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Molecular Docking Simulation; Protein Structure, Tertiary; Receptors, G-Protein-Coupled; Structure-Activity Relationship

Human GPR40 receptor (hGPR40), also known as free fatty-acid receptor 1 (FFAR1), is a G-protein-coupled receptor that binds long-chain free fatty acids to enhance glucose-dependent insulin secretion. Novel treatments for type-2 diabetes mellitus are therefore possible by targeting hGPR40 with partial or full agonists. TAK-875, or fasiglifam, is an orally available, potent and selective partial agonist of hGPR40 receptor, which reached phase III clinical trials for the potential treatment of type-2 diabetes mellitus. Data from clinical studies indicate that TAK-875, which is an ago-allosteric modulator of hGPR40 (ref. 3), demonstrates improved glycaemic control and low hypoglycaemic risk in diabetic patients. Here we report the crystal structure of hGPR40 receptor bound to TAK-875 at 2.3 Å resolution. The co-complex structure reveals a unique binding mode of TAK-875 and suggests that entry to the non-canonical binding pocket most probably occurs via the lipid bilayer. The atomic details of the extensive charge network in the ligand binding pocket reveal additional interactions not identified in previous studies and contribute to a clear understanding of TAK-875 binding to the receptor. The hGPR40-TAK-875 structure also provides insights into the plausible binding of multiple ligands to the receptor, which has been observed in radioligand binding and Ca(2+) influx assay studies. Comparison of the transmembrane helix architecture with other G-protein-coupled receptors suggests that the crystallized TAK-875-bound hGPR40 complex is in an inactive-like state.

Topics: Allosteric Regulation; Benzofurans; Binding Sites; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Drug Partial Agonism; Humans; Ligands; Lipid Bilayers; Models, Molecular; Receptors, G-Protein-Coupled; Structural Homology, Protein; Sulfones; Surface Properties

G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic β-cells. We previously identified (2,3-dihydro-1-benzofuran-3-yl)acetic acid derivative 2 as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on 2 yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 μM (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound 16 had the lowest lipophilicity. Metabolic analysis of 16 showed a long-acting PK profile due to high resistance to β-oxidation. Oral administration of 16 significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound 16 (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Tolerance Test; Hep G2 Cells; Humans; Insulin; Insulin Secretion; Male; Rats; Receptors, G-Protein-Coupled; Stereoisomerism; Sulfones

G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA(1)) is highly expressed in pancreatic β cells and mediates free fatty acid-induced insulin secretion. This study examined the pharmacological effects and potential for avoidance of lipotoxicity of [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate) (TAK-875), a novel, orally available, selective GPR40 agonist. Insulinoma cell lines and primary rat islets were used to assess the effects of TAK-875 in vitro. The in vivo effects of TAK-875 on postprandial hyperglycemia, fasting hyperglycemia, and normoglycemia were examined in type 2 diabetic and normal rats. In rat insulinoma INS-1 833/15 cells, TAK-875 increased intracellular inositol monophosphate and calcium concentration, consistent with activation of the Gqα signaling pathway. The insulinotropic action of TAK-875 (10 μM) in INS-1 833/15 and primary rat islets was glucose-dependent. Prolonged exposure of cytokine-sensitive INS-1 832/13 to TAK-875 for 72 h at pharmacologically active concentrations did not alter glucose-stimulated insulin secretion, insulin content, or caspase 3/7 activity, whereas prolonged exposure to palmitic or oleic acid impaired β cell function and survival. In an oral glucose tolerance test in type 2 diabetic N-STZ-1.5 rats, TAK-875 (1-10 mg/kg p.o.) showed a clear improvement in glucose tolerance and augmented insulin secretion. In addition, TAK-875 (10 mg/kg, p.o.) significantly augmented plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhanced insulin secretion nor caused hypoglycemia even at 30 mg/kg. TAK-875 enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of β cell toxicity.

Topics: Animals; Benzofurans; Blood Glucose; Calcium; Caspase 3; Caspase 7; Cell Survival; CHO Cells; Cricetinae; Cricetulus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fasting; Glucose; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Postprandial Period; Rats; Rats, Sprague-Dawley; 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