Search

G-protein-coupled receptor 40 (GPR40/FFA1/FFAR1), a clinically validated anti-diabetes target, enhances insulin secretion in type 2 diabetes. It is known that the effect of glucose-stimulated insulin secretion (GSIS) in pancreatic β cells is mediated primarily through Gq. However, in a recent study, it was found that GPR40 plays a role in both G protein-mediated and β-arrestin-mediated mechanisms, and fasiglifam (TAK-875), a partial GPR40 agonist discontinued in phase 3 clinical trials, induces insulin secretion by mediating β-arrestin rather than Gq. Therefore, by using stable GPR40 cell lines and β cells, we tried to confirm the signaling mechanism and efficacy of IDG-16177, which is being developed by Ildong Pharma in first-in-human study, as a GPR40 agonist. In cells expressing recombinant human, rat, and cynomolgus monkey GPR40, IDG-16177 dose-dependently increases intracellular free Ca2+ level, with EC50 of 114.3, 103.9, and 758.8 nM, respectively, showing no significant differences between human and rat (fasiglifam EC50= 75.2, 140.4, and 906.2 nM). IDG-16177 enhances β-arrestin recruitment, which has been shown to contribute to GPR40-mediated GSIS, with an EC50 of 68.0 nM and Emax of 99.4%, and is more efficacious and potent than fasiglifam (EC50= 154.0 nM; Emax= 88.0%). IDG-16177 exhibits EC50 of 0.8 nM and 110.6 nM, in inositol phosphate 1 (IP1) accumulation assay and extracellular signal-regulated kinase (ERK) activation assay, respectively. Although IDG-16177 shows no signal at the cAMP pathway like fasiglifam, IDG-16177 (0.1~3 μM)-treated group enhances more insulin secretion than fasiglifam (1~10 μM) in HIT-T15 β cells. These studies support the potential utility of IDG-16177 for the treatment of type 2 diabetes. Disclosure J. Yoon: None. Y. Jun: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. H. Song: None. D. Lee: None. J. Kim: None. D. Hong: None. C. Shin: None. E. Jang: None. J. Kim: None. S. Lee: None.

GLP-1R agonists comprise a growing class of agents that deliver unprecedented efficacy in the treatment of diabetes. We discovered promising compounds for the development of a novel small molecule GLP-1R agonist and examined their efficacy in cynomolgus monkey. The in vitro activities of the compounds were evaluated by measuring cAMP accumulation in cells expressing human GLP-1R. All compounds demonstrated potent cAMP accumulation of EC50 value below 20 nM, with one compound showing 1.5 nM. In addition, the compounds showed excellent selectivity against related class B GPCR, with no stimulatory activity on human GIP, GCG, and GLP-2 receptors. In the intravenous glucose tolerance test, according to the present disclosure, the compounds increased insulin secretion in cynomolgus monkey (dosed 50 mg/kg, p.o.), demonstrating their efficacy as orally available GLP-1 receptor agonists. Moreover, inhibitory effect on the hERG current was investigated and the compounds were shown to have favorable safety profile with IC50 values ranging from 34.6 to more than 100 μM. In conclusion, we discovered promising compounds which have potential to be developed as an orally active, non-peptide GLP-1R agonist for the treatment of type 2 diabetes with favorable safety profile regarding the hERG current. Disclosure A. Im: None. Y. Jun: None. E. Jang: None. Y. Yoo: None. W. Jeon: None. K. An: None. J. Park: None. D. Hong: None. I. Je: None. J. Kim: None. M. Chang: None. C. Hong: None. J. Shin: None. T. Sohn: None.

GPR40 has been considered a potential therapeutic target for type 2 diabetes because activation of GPR40 stimulates insulin secretion when glucose levels increased. Fasiglifam, a GPR40 agonist, was withdrawn from clinical development in Phase III due to DILI. Therefore, we evaluated the safety profiles of IDG-16177, a novel GPR40 agonist. The potential for IDG-16177 to have off-target effects was assessed in a panel of 173 binding assays. 10 μM IDG-16177 demonstrated activity (>50% inhibition) against DP, EP2, EP3 and EP4 with 81, 83, 57 and 67 % inhibition, respectively. In a functional assay against the same targets, IDG-16177 was inactive in agonist and antagonist mode except for DP with 62.2% activity inhibition at a concentration of 10 μM. IDG-16177 and fasiglifam showed the similar level of hepatotoxic response in HμRELToxTM assay. Formation of reactive metabolite and covalent binding to proteins was evaluated in human hepatocytes. IDG-16177 shows lower covalent binding burden at expected human efficacious dose (0.3~1 mg) than fasiglifam. Transporter inhibitory potential of IDG-16177 was assessed in hepatic transporter-expressing membrane vesicles. IDG-16177 and fasiglifam showed the similar inhibition level of BSEP, MRP2, MRP3, and MRP4. But clinically predicted plasma concentration of IDG-16177 is lower than that of fasiglifam, so the safety margin of IDG-16177 is wider than that of fasiglifam. A core battery of safety pharmacology was evaluated and IDG-16177 did not induce adverse effect in all studies. A 4-week toxicity study was conducted in rats and monkeys, and the liver was determined as the target organ in monkeys. The NOAEL was over 60-fold than in vivo efficacy dose. IDG-16177 was not genotoxic in Ames test, in vitro and in vivo micronucleus test. And no phototoxicity was observed in in vitro 3T3 NRU study. These results shows that the potential for IDG-16177, a safe and effective GPR40 agonist, to treat patients with type 2 diabetes. Disclosure J. Yoon: None. J. Kim: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. H. Song: None. J. Kim: None. S. Lee: None. C. Shin: None. Y. Jun: None. D. Hong: None. D. Lee: None. E. Jang: None.

GPR40/FFAR1 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. GPR40 agonists are known to stimulate insulin secretion and reduce circulating glucose levels in a glucose-dependent manner. Currently, IDG-16177, as a GPR40 agonist, is being developed by ildong Pharma in first-in-human study. IDG-16177 is a high potency and orally available small molecule agonist. IDG-16177 confirmed linear pharmacokinetic properties and is more potent than fasiglifam from in vivo studies. The oral bioavailability of IDG-16177 was 84.3, 75.4, and 71% in mice, rats, and monkeys, showing high oral absolute bioavailability in preclinical species. The Cmax and AUC values of IDG-16177 increased in a dose-proportional manner in a dose range of 0.3 to 10 mg/kg in mice and rats and 0.3 to 3 mg/kg in monkeys. In vivo long-term glucose-lowering effect was determined by oral glucose tolerance test (OGTT) in Sprague-Dawley (SD) rats and Otsuka Long-Evans Tokushima Fatty (OLETF) rats, respectively. IDG-16177 showed dose-dependently improvement of glucose tolerance in a multiple dosing study using SD and OLETF rats. In both in vivo tests, IDG-16177 0.3 mg/kg showed similar effective in glucose tolerance fasiglifam 10 mg/kg, respectively. In addition, IDG-16177 had a positive effect on fasting blood glucose, insulin, and glucagon in the long-term administration of OLETF rats. In these study, Cmax,ss of IDG-16177 showed approximately 60 times lower than those of fasiglifam and AUCss of IDG-16177 showed approximately 170 times lower than those of fasiglifam. In another study, the Glucose-stimulated insulin secretion effect of IDG-16177 was assessed in Male SD rat. IDG-16177 1 mg/kg showed similar effective in insulin secretion fasiglifam 10 mg/kg. These results show that IDG-16177 might be an effective drug candidate for treatment of type 2 diabetes. Disclosure J. Yoon: None. Y. Jun: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. D. Lee: None. J. Kim: None. D. Hong: None. C. Shin: None. E. Jang: None. J. Kim: None. H. Song: None. S. Lee: None.

GPR40/FFAR1 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. GPR40 agonists are known to stimulate insulin secretion and reduce circulating glucose levels in a glucose-dependent manner. We investigated IDG-16177(ID11014A) as a GPR40 agonist and confirmed this drug has linear pharmacokinetic properties and is more potent than fasiglifam from in vitro and in vivo studies. In vitro metabolic stability of IDG-16177 was evaluated in mouse, rat, dog, monkey and human microsomes. IDG-16177 was metabolized mainly by CYPs in mouse, rat, monkey and human while it was metabolized mainly by UGTs in dog. Oral bioavailability of IDG-16177 was 88.1 ~ 109.9% in SD rats. The Cmax and AUC values of IDG-16177 increased in a dose-proportional manner in the dose range of 1 ~ 10 mg/kg. IDG-16177 was also well exposed in monkeys after 3 mg/kg administration. Glucose lowering effect was determined by oral glucose tolerance test (OGTT) in Sprague-Dawley (SD) rats and in various type 2 diabetes rats, respectively. IDG-16177 showed dose-dependently improvement of glucose tolerance in a single dosing study using SD and Goto-Kakizaki (GK) rats. IDG-16177 1mg/kg showed more effective in glucose tolerance than fasiglifam 10mg/kg in repeated dosing study of Zucker Diabetic Fatty (ZDF) rats. In this study, Cmax,ss and AUCss of IDG-16177 showed approximately 10 times lower than those of fasiglifam. These results show that IDG-16177 might be an effective drug candidate for treatment of type 2 diabetes. Disclosure J. Yoon: None. D. Kim: None. D. Lee: None. K. An: None. M. Lee: None. C. Hong: None. D. Hong: None. H. Kwak: None. I. Je: None. H. Song: None.

GPR40 is one of the most prominent targets for the treatment of type 2 diabetes (T2DM), and has its role in insulin secretion via blood-glucose-dependent manner with a minimum risk of hypoglycemia. In order to discover novel antidiabetics bearing these benefits, we screened various derivatives with two distinct pharmacophores. Both series displayed potent agonistic activities for GPR40 in vitro functional assay. Through additional ADME and in vivo efficacy evaluations, we identified the potent hit candidate 2j as a novel GPR40 agonist.