作者
Mark Zak,Bianca M. Liederer,Deepak Sampath,Po‐wai Yuen,Kenneth W. Bair,Timm Baumeister,Alexandre J. Buckmelter,Karl H. Clodfelter,Elaine Cheng,Lisa Crocker,Bang Fu,Bingsong Han,Guangkun Li,Yew Kam Ho,Jian Lin,Xiongcai Liu,Justin Q. Ly,Thomas G. O’Brien,Dominic J. Reynolds,Nicholas J. Skelton,Chase C. Smith,Suzanne Tay,Weiru Wang,Zhongguo Wang,Yang Xiao,Lei Zhang,Gui‐Ling Zhao,Xiaozhang Zheng,Peter S. Dragovich
摘要
Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering c Log D7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.