The synthesized methoxyamide derivatives were evaluated for

The synthesized -methoxyamide derivatives were evaluated for in vitro as GPR119 agonists (, , ) whereas GSK1292263 (II in ) was used as the reference standard. To identify novel sulfone or tetrazole surrogates, diverse functional groups including amide, -sulfonyl amide, hydrazide, -methoxy--methylamide, -methoxyamide, -ethoxyamide, -benzyloxyamide, and 1,2-oxazinane were introduced on thienopyrimidine and pyridine backbones. Thienopyrimidine ( and pyridine () moieties are known linker groups in structures of GPR119 agonists., Introduction of -methoxy--methylamide as the polar head resulted in opioid receptors , showing potency (% activation relative to GSK1292263 (100%) at 1μM) comparable to the reference compound (105% activation at 1μM) and good agonistic activity (EC 98nM) (). In addition, compound showed moderate potency and good agonistic activity (EC 156nM). These results indicated that -methoxyamide could be a suitable methylsulfonyl/tetrazole surrogate. Next, -methoxy--methylamide group was replaced with -methoxyamide (), -ethoxyamide (), -benzyloxy amide ( and ) and 1,2-oxazinane (); however, these various derivatives showed reduced potency compared to compound . Based on data shown in , thienopyrimidine scaffold was replaced with pyridine (, and the activity data summarized in . As shown in , most of the pyridine compounds showed similar potency and activity to thienopyrimidine analogs. Compounds , , and showed good to moderate potency and moderate agonistic activity (EC 150–350nM). Meanwhile, compounds and substituted with benzyloxyamide and 1,2-oxazinane showed reduced potency, similar to their thienopyrimidine analogs. We considered that -methoxy--methylamide was the most appropriate functional group from the activity data as shown in , . Therefore, herein supposed to need to modify other parts by fixing -methoxy--methylamide part. As shown in , 2-fluoro aryl substituents increased the agonistic activity of thienopyrimidine compounds. Compounds , and showed good in vitro activities with an EC of 53 and 67nM, compared to , and . Compounds , , , and in which methylamino group of the thienopyrimidine scaffold was replaced with oxygen showed moderately improved potency and agonistic activity compared to methylamine analogs , , , and . Additionally, pyridine compounds , , and showed potential for further evaluation with significantly improved agonistic activity (up to 5-fold) and potency relative to compounds , , and which lack of fluorine. From in vitro data, we chose four representative compounds (, , and ) and performed in vivo oral glucose tolerance tests (OGTT) (data not shown). Among them, compound showed good glucose lowering efficacy, therefore it was selected as a prototype compound. As shown in , compound significantly reduced plasma glucose levels (determined using AUC) in OGTT at doses of 30 and 50mg/kg. Differentiated NCI-H716 cells, which express high levels of GLP-1, represent a useful cellular model for regulation of GLP-1 secretion in humans. Compound (at 100 nM) significantly stimulated GLP-1 secretion in NCI-H716 cells (). In conclusion, we identified -methoxy--methylamide as a novel methanesulfonyl/tetrazole surrogate in structures of GPR119 agonists. Several compounds showed good agonistic activity (EC<100nM) and potency. Among them, compound showed good in vitro activity, in vivo efficacy (OGTT) as well as GLP-1 secretion in intestinal cells. Acknowledgments
Diabetes can cause serious health complications such as cardiovascular disease, blindness and kidney failure. It is becoming more common in the United States and worldwide. For example, from 1980 through 2014, the number of Americans with diagnosed diabetes has increased fourfold (from 5.5million to 22.0million). Among diabetic patients, a majority (approximately 90–95%) have type 2 diabetes (T2D). Therefore, more effective and safer therapies for type 2 diabetes are needed. G protein-coupled receptor 119 (GPR119) agonists have emerged as a potential new approach for the treatment of type 2 diabetes.