Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000 Rahway, NJ 07065, USA.
Bioorg Med Chem Lett. 2011 May 1;21(9):2665-9. doi: 10.1016/j.bmcl.2010.12.086. Epub 2010 Dec 22.
Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC(50)=3600 nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined with the termini SAR optimizations yielded a potent and highly selective agonist suitable for further preclinical development (58).
对默克公司的样本采集进行筛选后，鉴定出化合物 1 是一种弱效的 GPR119 激动剂（hEC(50)=3600nM）。对 1 进行双末端优化得到化合物 36，其效力、选择性和配方特性得到改善，但中等的物理性质（PP）限制了其应用。设计一个含有环丙基限制的新核心，进一步改善了 PP，当与末端 SAR 优化相结合时，得到了一种有效且高度选择性的激动剂，适合进一步的临床前开发（58）。
