Design of Potent and Orally Active GPR119 Agonists for the Treatment of Type II Diabetes.

摘要: We report herein the design and synthesis of a series potent selective GPR119 agonists. Our objective was to develop agonist with properties that were suitable for fixed-dose combination DPP4 inhibitor. Starting from phenoxy analogue (1), medicinal chemistry efforts directed toward reducing half-life increasing solubility led benzyloxy analogues. Compound 28 chosen further profiling because its favorable physicochemical excellent potency across species. This compound exhibited clean off-target profile in counterscreens good vivo efficacy mouse oGTT.