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

Mark Zak; Bianca M Liederer; Deepak Sampath; Po-Wai Yuen; Kenneth W Bair; Timm Baumeister; Alexandre J Buckmelter; Karl H Clodfelter; Eric Cheng; Lisa Crocker; Bang Fu; Bingsong Han; Guangkun Li; Yen-Ching Ho; Jian Lin; Xiongcai Liu; Justin Ly; Thomas O'Brien; Dominic J Reynolds; Nicholas Skelton; Chase C Smith; Suzanne Tay; Weiru Wang; Zhongguo Wang; Yang Xiao; Lei Zhang; Guiling Zhao; Xiaozhang Zheng; Peter S Dragovich

doi:10.1016/j.bmcl.2014.12.026

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

Bioorg Med Chem Lett. 2015 Feb 1;25(3):529-41. doi: 10.1016/j.bmcl.2014.12.026. Epub 2014 Dec 17.

Authors

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

Affiliations

¹ Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: mzak@gene.com.
² Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
³ Pharmaron Beijing Co. Ltd, 6 Taihe Road, BDA, Beijing 100176, PR China.
⁴ Forma Therapeutics Inc., 500 Arsenal Street, Watertown, MA 02472, USA.

PMID: 25556090
DOI: 10.1016/j.bmcl.2014.12.026

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.

Keywords: Aqueous solubility; CYP TDI; Cytochrome P450 time-dependent inhibition; NAMPT; Nicotinamide phosphoribosyltransferase; Tumor metabolism.

MeSH terms

Animals
Binding Sites
Cell Line, Tumor
Cell Membrane Permeability / drug effects
Cell Proliferation / drug effects
Crystallography, X-Ray
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
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
Neoplasms / drug therapy
Neoplasms / pathology
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
Water / chemistry

Substances

Cytochrome P-450 CYP3A Inhibitors
Enzyme Inhibitors
Pyrimidines
Water
Cytochrome P-450 CYP3A
Nicotinamide Phosphoribosyltransferase
pyrimidine