Herein, we describe the discovery, synthesis, and evaluation of a novel series of spiro[chromane-2,4′-piperidine] derivatives as G-protein-coupled receptor 119 agonists. Their initial design exploited the conformational restriction in the linker-to-tail moiety, which was a key concept in this study, to give lead compound 11 (EC₅₀ = 369 nM, E_max = 82%). An extensive structure–activity relationship study resulted in the identification of the optimized drug candidate (R)-29 (EC₅₀ = 54 nM, E_max = 181%). The defining structural features of the series were a terminal benzyl-type bulky substituent and a methylene linker between the sulfonyl and phenyl groups, both of which were in the head moiety as well as the spiro-type scaffold in the linker-to-tail moiety. An in vivo oral glucose-tolerance test using C57BL/6N mice showed that (R)-29 reduced glucose excursion at a dose of 3 mg/kg in a dose-dependent manner.

在本文中，我们描述了作为G蛋白偶联受体119激动剂的螺[chromane-2,4'-哌啶]衍生物系列的发现，合成和评估。他们的最初设计利用了接头到尾部的构象限制，这是本研究的关键概念，得到了前导化合物11（EC ₅₀  = 369 nM，E _max  = 82％）。广泛的构效关系研究确定了最佳候选药物（R）-29（EC ₅₀  = 54 nM，E _max = 181％）。该系列的定义结构特征是末端苄基型大体积取代基和磺酰基和苯基之间的亚甲基接头，两者均在头部和接头至尾部的螺旋型支架中。使用C57BL / 6N小鼠进行的体内口服葡萄糖耐量测试表明，（R）-29以3 mg / kg的剂量呈剂量依赖性地降低了葡萄糖偏移。