Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility

[Display omitted] 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 im...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-02, Vol.25 (3), p.529-541
Hauptverfasser:	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.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Aqueous solubility Binding Sites Cell Line, Tumor Cell Membrane Permeability - drug effects Cell Proliferation - drug effects Crystallography, X-Ray CYP TDI Cytochrome P-450 CYP3A - chemistry Cytochrome P-450 CYP3A - metabolism Cytochrome P-450 CYP3A Inhibitors - chemistry Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics Cytochrome P-450 CYP3A Inhibitors - toxicity Cytochrome P450 time-dependent inhibition Dogs Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - therapeutic use Female Half-Life Humans Kinetics Madin Darby Canine Kidney Cells Mice Mice, Nude Molecular Dynamics Simulation NAMPT Neoplasms - drug therapy Neoplasms - pathology Nicotinamide phosphoribosyltransferase Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors Nicotinamide Phosphoribosyltransferase - metabolism Protein Binding Protein Structure, Tertiary Pyrimidines - chemistry Pyrimidines - therapeutic use Pyrimidines - toxicity Solubility Structure-Activity Relationship Thermodynamics Transplantation, Heterologous Tumor metabolism Water - chemistry
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Zusammenfassung:	[Display omitted] 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2014.12.026