Yu, Ming; Lizarzaburu, Mike; Motani, Alykhan; Fu, Zice; Du, Xiaohui; Liu, Jiwen; Jiao, Xianyun; Lai, SuJen; Fan, Peter; Fu, Angela; Liu, Qingxiang; Murakoshi, Michiko; Nara, Futoshi; Oda, Kozo; Okuyama, Ryo; Reagan, Jeff D.; Watanabe, Nobuaki; Yamazaki, Mami; Xiong, Yumei; Zhang, Ying; Zhuang, Run; Lin, Daniel C.-H.; Houze, Jonathan B.; Medina, Julio C.; Li, Leping published the artcile< Aminopyrazole-Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies>, SDS of cas: 1003-32-3, the main research area is amrinone phenylalanine carboxylic acid preparation GPR142 agonist structure design; pharmacokinetics bioavailability diabetes amrinone phenylalanine carboxylic acid antidiabetic prodrug; glucose tolerance insulin secretagogue human islet transplant CYP450 hERG; GPR142 agonist; aminopyrazole−phenylalanine; human islet transplant; insulin secretagogue; oral glucose tolerance test; prodrug; type 2 diabetes.
Herein, we report the lead optimization of amrinone-phenylalanine based GPR142 agonists. Structure-activity relationship studies led to the discovery of aminopyrazole-phenylalanine carboxylic acid I, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P 450 or hERG liability. Compound I, together with its orally bioavailable Et ester prodrug II, were found to be suitable for in vivo proof-of-concept studies. Compound II displayed good efficacy in a mouse oral glucose tolerance test (OGTT). CompoundI showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets.
ACS Medicinal Chemistry Letters published new progress about Antidiabetic agents. 1003-32-3 belongs to class thiazole, and the molecular formula is C4H3NOS, SDS of cas: 1003-32-3.
Referemce:
Thiazole | C3H3NS – PubChem,
Thiazole | chemical compound | Britannica