Koshizawa Tomoaki, Morimoto Toshiharu, Watanabe Gen, Watanabe Toshiaki, Yamasaki Nao, Sawada Yoshikazu, Fukuda Tomoaki, Okuda Ayumu, Shibuya Kimiyuki, Ohgiya Tadaaki
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., LTD., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., LTD., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
Bioorg Med Chem Lett. 2017 Aug 1;27(15):3249-3253. doi: 10.1016/j.bmcl.2017.06.034. Epub 2017 Jun 13.
We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC=129nM) was improved by replacing the intramolecular hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compound 12 (EC=53nM). Optimized compound 26, which was identified by the further optimization of 12, exhibited potent activity (EC=42nM) with improved clearance in liver microsomes and induced a 33% reduction in blood glucose area under the curve at a dose of 10mg/kg in an oral glucose tolerance test in C57BL/6N mice.
我们描述了一系列新型呋[3,2 - d]嘧啶作为G蛋白偶联受体119激动剂的发现与优化过程。通过将头部基团中氟原子与苯胺氢之间的分子内氢键替换为共价C - C键以增强构象限制，4的激动活性（EC = 129 nM）得到了改善，从而得到先导化合物12（EC = 53 nM）。通过对12的进一步优化确定的优化化合物26表现出强效活性（EC = 42 nM），在肝微粒体中的清除率得到改善，并且在C57BL / 6N小鼠的口服葡萄糖耐量试验中，以10 mg / kg的剂量给药时，可使血糖曲线下面积降低33%。
