Yasuhiro Yonetoku

AS1907417, a novel GPR119 agonist, as an insulinotropic and β-cell preservative agent for the treatment of type 2 diabetes.

G-protein-coupled receptor (GPR) 119 is involved in glucose-stimulated insulin secretion (GSIS) and represents a promising target for the treatment of type 2 diabetes as it is highly expressed in pancreatic β-cells. Although a number of oral GPR119 agonists have been developed, their inability to adequately directly preserve β-cell function limits their effectiveness. Here, we evaluated the therapeutic potential of a novel small-molecule GPR119 agonist, AS1907417, which represents a modified form of a 2,4,6-tri-substituted pyrimidine core agonist, AS1269574, we previously identified. The exposure of HEK293 cells expressing human GPR119, NIT-1 cells expressing human insulin promoter, and the pancreatic β-cell line MIN-6-B1 to AS1907417, enhanced intracellular cAMP, GSIS, and human insulin promoter activity, respectively. In in vivo experiments involving fasted normal mice, a single dose of AS1907417 improved glucose tolerance, but did not affect plasma glucose or insulin levels. Twice-daily doses of AS1907417 for 4weeks in diabetic db/db, aged db/db mice, ob/ob mice, and Zucker diabetic fatty rats reduced hemoglobin A1c levels by 1.6%, 0.8%, 1.5%, and 0.9%, respectively. In db/db mice, AS1907417 improved plasma glucose, plasma insulin, pancreatic insulin content, lipid profiles, and increased pancreatic insulin and pancreatic and duodenal homeobox 1 (PDX-1) mRNA levels. These data demonstrate that novel GPR119 agonist AS1907417 not only effectively controls glucose levels, but also preserves pancreatic β-cell function. We therefore propose that AS1907417 represents a new type of antihyperglycemic agent with promising potential for the effective treatment of type 2 diabetes.

Novel potent and selective Ca2+ release-activated Ca2+ (CRAC) channel inhibitors. Part 3: Synthesis and CRAC channel inhibitory activity of 4'-[(trifluoromethyl)pyrazol-1-yl]carboxanilides

From a series of 4-[(trifluoromethyl)pyrazol-1-yl]carboxanilides derived from 4-methyl-4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1,2,3-thiadiazole-5-carboxanilide, one inhibited thapsigargin-induced Ca2+ influx in Jurkat T cells (IC(50)=77 nM) and exhibited high selectivity for the CRAC channel over the VOC channel (index: >130). Another acted as an inhibitor for both T lymphocyte activation-induced diseases and ovalbumin-induced airway eosinophilia in rats (ED(50)=1.3 mg/kg) p.o.

The role of small molecule GPR119 agonist, AS1535907, in glucose-stimulated insulin secretion and pancreatic β-cell function

Aim: AS1535907, a small molecule agonist of GPR119, was assessed for its glucose‐stimulated insulin secretory activity and pancreatic β‐cell function in type 2 diabetes.

Novel GPR119 agonist AS1535907 contributes to first-phase insulin secretion in rat perfused pancreas and diabetic db/db mice

G protein-coupled receptor (GPR) 119 is highly expressed in pancreatic β-cells and enhances the effect of glucose-stimulated insulin secretion (GSIS) on activation. The development of an oral GPR119 agonist that specifically targets the first phase of GSIS represents a promising strategy for the treatment of type 2 diabetes. In the present study, we evaluated the therapeutic potential of a novel small molecule GPR119 agonist, AS1535907, which was modified from the previously identified 2,4,6-tri-substituted pyrimidine core agonist AS1269574. AS1535907 displayed an EC50 value of 4.8 μM in HEK293 cells stably expressing human GPR119 and stimulated insulin secretion in rat islets only under high-glucose (16.8 mM) conditions. In isolated perfused pancreata from normal rats, AS1535907 enhanced the first phase of insulin secretion at 16.8 mM glucose, but had no effect at 2.8mM glucose. In contrast, the sulfonylurea glibenclamide predominantly induced insulin release in the second phase at 16.8 mM glucose and also markedly stimulated insulin secretion at 2.8 mM glucose. In in vivo studies, a single 10 μM administration of AS1535907 to diabetic db/db mice reduced blood glucose levels due to the rapid secretion of insulin secretion following oral glucose loading. These results demonstrate that GPR119 agonist AS1535907 has the ability to stimulate the first phase of GSIS, which is important for preventing the development of postprandial hypoglycemia. In conclusion, the GPR119 agonist AS1535907 induces a more rapid and physiological pattern of insulin release than glibenclamide, and represents a novel strategy for the treatment of type 2 diabetes.

Synthesis and structure–activity relationship of 4-amino-2-phenylpyrimidine derivatives as a series of novel GPR119 agonists

Through preparation and examination of a series of novel 4-amino-2-phenylpyrimidine derivatives as agonists for GPR119, we identified 2-(4-bromophenyl)-6-methyl-N-[2-(1-oxidopyridin-3-yl)ethyl]pyrimidin-4-amine (9t). Compound 9t improved glucose tolerance in mice following oral administration and showed good pharmacokinetic profiles in rats.

Synthesis of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives as inhibitors of human liver glycogen phosphorylase a.

A series of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives were prepared and evaluated as inhibitors of human liver glycogen phosphorylase a (hLGPa). One compound, 5-chloro-N-[4-(1,2-dihydroxyethyl)phenyl]-1H-indole-2-carboxamide (2f), inhibited hLGPa with an IC(50) of 0.90microM. The pyridine analogue of 2f showed inhibitory activity of glucagon-induced glucose output in cultured primary hepatocytes with an IC(50) of 0.62microM and oral hypoglycemic activity in diabetic db/db mice. Crystallographic determination of the complex of 2f with hLGPa showed binding of the inhibitor in a solvent cavity at the dimer interface, with the two hydroxyl groups making favorable electrostatic interactions with hLGPa.

Novel GPR119 agonist AS1669058 potentiates insulin secretion from rat islets and has potent anti-diabetic effects in ICR and diabetic db/db mice.

AIMSnG-protein-coupled receptor 119 (GPR119), mainly expressed in pancreatic β-cells, represents a new target for treating type 2 diabetes. GPR119 agonist is known to induce insulin secretion in a glucose-dependent manner by elevating intracellular cAMP concentrations. This study mainly examined the anti-hyperglycemic effect of a novel candidate small-molecule GPR119 agonist AS1669058 2-(4-bromo-2,5-difluorophenyl)-6-methyl-N-[2-(1-oxidopyridin-3-yl)ethyl]pyrimidin-4-amine ethanedioate on ICR mice and diabetic db/db mice.nnnMAIN METHODSnWe measured blood glucose, plasma insulin, and insulin content in the pancreas after repeated administration of AS1669058 to db/db mice twice daily for one week.nnnKEY FINDINGSnUnder high-concentration glucose conditions, AS1669058 induced insulin secretion in a dose-dependent manner in the hamster pancreatic β-cell line HIT-T15 and in rat pancreatic islets. In addition, AS1669058 increased human insulin promoter activity in NIT-1 cells. In in vivo studies, a single administration of AS1669058 (1 mg/kg) in ICR mice improved oral glucose tolerance based on insulin secretion. Further, 1-week repeated treatment (3 mg/kg, twice daily) in diabetic db/db mice significantly reduced blood glucose levels and tended to increase insulin content in the pancreas.nnnSIGNIFICANCEnThese results suggest that AS1669058 has promising potential as an extremely more effective anti-hyperglycemic agent than other compounds we previously reported as GPR119 agonists.

Synthesis and structure–activity relationship of fused-pyrimidine derivatives as a series of novel GPR119 agonists

A series of fused-pyrimidine derivatives have been discovered as potent and orally active GPR119 agonists. A combination of the fused-pyrimidine structure and 4-chloro-2,5-difluorophenyl group provided the 5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide derivative 14a as a highly potent GPR119 agonist. Further optimization of the amino group at the 4-position in the pyrimidine ring led to the identification of 2-{1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl}acetamide (16b) as an advanced analog. Compound 16b was found to have extremely potent agonistic activity and improved glucose tolerance at 0.1 mg/kg po in mice. We consider compound 16b and its analogs to have clear utility in exploring the practicality of GPR119 agonists as potential therapeutic agents for the treatment of type 2 diabetes mellitus.

Discovery and biological evaluation of novel 4-amino-2-phenylpyrimidine derivatives as potent and orally active GPR119 agonists

Novel 4-amino-2-phenylpyrimidine derivatives were synthesized and evaluated as GPR119 agonists. Optimization of the substituents on the phenyl ring at the 2-position and the amino group at the 4-position led to the identification of 3,4-dihalogenated and 2,4,5-trihalogenated phenyl derivatives showing potent GPR119 agonistic activity. The advanced analog (2R)-3-{[2-(4-chloro-2,5-difluorophenyl)-6-ethylpyrimidin-4-yl]amino}propane-1,2-diol (24g) was found to improve glucose tolerance at 1mg/kg po in mice and to show excellent pharmacokinetic profiles in mice and monkeys. Compound 24g also showed an excellent antidiabetic effect in diabetic kk/Ay mice after one week of single daily treatment. These results demonstrate that novel GPR119 agonist 24g improves glucose tolerance not only by enhancing glucose-dependent insulin secretion but also by preserving pancreatic β-cell function.

Synthesis and pharmacological evaluation of bis-3-(3,4-dichlorophenyl)acrylamide derivatives as glycogen phosphorylase inhibitors

During our research using a high-throughput screening system for discovery of a new class of human liver glycogen phosphorylase a (hLGPa) inhibitors, a series of 3-(3,4-dichlorophenyl)acrylamide derivatives were synthesized, and their inhibitory activities toward hLGPa were evaluated. Among the derivatives, (2E,2E)-N,N-pentane-1,5-diylbis[3-(3,4-dichlorophenyl)acrylamide] (6c) inhibited hLGPa with an IC(50) value of 0.023 microM. An X-ray crystallographic study of the enzyme-6c complex showed that the inhibitor is bound at the dimer interface site, where the 3,4-dichlorophenyl moiety interacts hydrophobically with the enzyme.