Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
Bioorg Med Chem Lett. 2014 Feb 15;24(4):1133-7. doi: 10.1016/j.bmcl.2013.12.127. Epub 2014 Jan 8.
We describe the discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel agonists of GPR119. Previously described aniline 2 had suboptimal efficacy in signaling assays using cynomolgus monkey (cyno) GPR119 making evaluation of the target in preclinical models difficult. Replacement of the aniline ring with a tetrahydroquinoline ring constrained the rotation of the aniline C-N bond and gave compounds with increased efficacy on human and cyno receptors. Additional optimization led to the discovery of 10, which possesses higher free fraction in plasma and improved pharmacokinetic properties in rat and cyno compared to 2.
我们描述了 5-(2-((1-(苯磺酰基)-1,2,3,4-四氢喹啉-7-基)氧基)吡啶-4-基)-1,2,4-恶二唑类作为 GPR119 的新型激动剂的发现和优化。以前描述的苯胺 2 在使用食蟹猴 (cyno) GPR119 的信号检测试验中的功效不佳，使得在临床前模型中评估该靶标变得困难。用四氢喹啉环取代苯胺环限制了苯胺 C-N 键的旋转，从而使化合物对人和 cyno 受体的功效增强。进一步的优化导致了 10 的发现，与 2 相比，10 在血浆中的游离分数更高，在大鼠和 cyno 中的药代动力学性质也得到了改善。
