Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Bioorg Med Chem Lett. 2011 Jun 1;21(11):3290-6. doi: 10.1016/j.bmcl.2011.04.035. Epub 2011 Apr 14.
The lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold are described. Extensive structure-activity relationship (SAR) studies of the lead compound 20f led to the identification of compound 36j as a potent, single digit nanomolar GPR119 agonist with high agonist activity. Compound 36j was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test and increased plasma insulin levels in a rat hyperglycemic model. It showed good to excellent pharmacokinetic properties in rats and monkeys and no untoward activities in counter-screen assays. Compound 36j demonstrated an attractive in vitro and in vivo profile for further development.
本文描述了一系列含有诺特醇骨架的 GPR119 激动剂的先导优化研究。对先导化合物 20f 进行了广泛的构效关系（SAR）研究，确定了化合物 36j 为一种有效的、单位数纳摩尔级的 GPR119 激动剂，具有很高的激动活性。化合物 36j 在小鼠口服葡萄糖耐量试验中具有降低血糖水平的作用，并在大鼠高血糖模型中增加血浆胰岛素水平。它在大鼠和猴子体内具有良好到优秀的药代动力学特性，在反向筛选试验中没有不良反应。化合物 36j 在体外和体内都表现出有吸引力的特性，适合进一步开发。
