Liu Ping, Hu Zhiyong, DuBois Byron G, Moyes Christopher R, Hunter David N, Zhu Cheng, Kar Nam Fung, Zhu Yuping, Garfunkle Joie, Kang Ling, Chicchi Gary, Ehrhardt Anka, Woods Andrea, Seo Toru, Woods Morgan, van Heek Margaret, Dingley Karen H, Pang Jianmei, Salituro Gino M, Powell Joyce, Terebetski Jenna L, Hornak Viktor, Campeau Louis-Charles, Lamberson Joe, Ujjainwalla Fez, Miller Michael, Stamford Andrew, Wood Harold B, Kowalski Timothy, Nargund Ravi P, Edmondson Scott D
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
ACS Med Chem Lett. 2015 Jul 10;6(8):936-41. doi: 10.1021/acsmedchemlett.5b00207. eCollection 2015 Aug 13.
We report herein the design and synthesis of a series of potent and selective GPR119 agonists. Our objective was to develop a GPR119 agonist with properties that were suitable for fixed-dose combination with a DPP4 inhibitor. Starting from a phenoxy analogue (1), medicinal chemistry efforts directed toward reducing half-life and increasing solubility led to the synthesis of a series of benzyloxy analogues. Compound 28 was chosen for further profiling because of its favorable physicochemical properties and excellent GPR119 potency across species. This compound exhibited a clean off-target profile in counterscreens and good in vivo efficacy in mouse oGTT.
我们在此报告一系列强效且选择性的GPR119激动剂的设计与合成。我们的目标是开发一种具有适合与二肽基肽酶4（DPP4）抑制剂进行固定剂量联合用药特性的GPR119激动剂。从苯氧基类似物（1）开始，旨在降低半衰期并提高溶解度的药物化学研究工作导致了一系列苄氧基类似物的合成。化合物28因其良好的物理化学性质和在不同物种中优异的GPR119活性而被选作进一步研究。该化合物在反筛选中显示出清晰的脱靶特征，并且在小鼠口服葡萄糖耐量试验（oGTT）中具有良好的体内疗效。
