1453175-45-5Relevant articles and documents
Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility
Zak, Mark,Liederer, Bianca M.,Sampath, Deepak,Yuen, Po-Wai,Bair, Kenneth W.,Baumeister, Timm,Buckmelter, Alexandre J.,Clodfelter, Karl H.,Cheng, Eric,Crocker, Lisa,Fu, Bang,Han, Bingsong,Li, Guangkun,Ho, Yen-Ching,Lin, Jian,Liu, Xiongcai,Ly, Justin,O'Brien, Thomas,Reynolds, Dominic J.,Skelton, Nicholas,Smith, Chase C.,Tay, Suzanne,Wang, Weiru,Wang, Zhongguo,Xiao, Yang,Zhang, Lei,Zhao, Guiling,Zheng, Xiaozhang,Dragovich, Peter S.
, p. 529 - 541 (2015/03/05)
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.
