Naidu B Narasimhulu, Walker Michael A, Sorenson Margaret E, Ueda Yasutsugu, Matiskella John D, Connolly Timothy P, Dicker Ira B, Lin Zeyu, Bollini Sagarika, Terry Brian J, Higley Helen, Zheng Ming, Parker Dawn D, Wu Dedong, Adams Stephen, Krystal Mark R, Meanwell Nicholas A
Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
Bioorg Med Chem Lett. 2018 Jul 1;28(12):2124-2130. doi: 10.1016/j.bmcl.2018.05.027. Epub 2018 May 14.
BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials.
BMS-707035是一种HIV-1整合酶链转移抑制剂（INSTI），它是通过在构效关系（SAR）和化合物10的单晶X射线结构指导下对N-甲基嘧啶酮羧酰胺进行系统优化而发现的。据推测，具有饱和C2取代基的N-甲基嘧啶酮羧酰胺出人意料的有利特性可能部分归因于C2取代基与嘧啶酮核心之间的几何关系。化合物10的单晶X射线结构为这一推理提供了支持，并指导了螺环系列12的设计，进而导致了吗啉基稠合嘧啶酮系列13的发现。与相应的螺环类似物相比，从这个双环骨架衍生的几种羧酰胺显示出改善的抗病毒活性和药代动力学特性。基于出色的抗病毒活性、临床前特性以及可接受的体外和体内毒性特性，选择了13a（BMS-707035）推进到I期临床试验。
