| Literature DB >> 25556090 |
Mark Zak1, Bianca M Liederer2, Deepak Sampath2, Po-Wai Yuen3, Kenneth W Bair4, Timm Baumeister4, Alexandre J Buckmelter4, Karl H Clodfelter4, Eric Cheng2, Lisa Crocker2, Bang Fu3, Bingsong Han4, Guangkun Li3, Yen-Ching Ho4, Jian Lin4, Xiongcai Liu3, Justin Ly2, Thomas O'Brien2, Dominic J Reynolds4, Nicholas Skelton2, Chase C Smith4, Suzanne Tay2, Weiru Wang2, Zhongguo Wang4, Yang Xiao2, Lei Zhang3, Guiling Zhao2, Xiaozhang Zheng4, Peter S Dragovich2.
Abstract
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 cLogD7.4 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.Entities:
Keywords: Aqueous solubility; CYP TDI; Cytochrome P450 time-dependent inhibition; NAMPT; Nicotinamide phosphoribosyltransferase; Tumor metabolism
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Year: 2014 PMID： 25556090 DOI： 10.1016/j.bmcl.2014.12.026
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823