title: Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility.
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.
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: mzak@gene.com.
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.affiliation: Pharmaron Beijing Co. Ltd, 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Po-Wai
authors.initials: PW
authors.lastname: Yuen
authors.affiliation: Forma Therapeutics Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Bair
authors.affiliation: Forma Therapeutics Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Timm
authors.initials: T
authors.lastname: Baumeister
authors.affiliation: Forma Therapeutics Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Alexandre J
authors.initials: AJ
authors.lastname: Buckmelter
authors.affiliation: Forma Therapeutics Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Karl H
authors.initials: KH
authors.lastname: Clodfelter
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Cheng
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Crocker
authors.affiliation: Pharmaron Beijing Co. Ltd, 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Bang
authors.initials: B
authors.lastname: Fu
authors.affiliation: Forma Therapeutics Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Bingsong
authors.initials: B
authors.lastname: Han
authors.affiliation: Pharmaron Beijing Co. Ltd, 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Guangkun
authors.initials: G
authors.lastname: Li
authors.affiliation: Forma Therapeutics Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Yen-Ching
authors.initials: YC
authors.lastname: Ho
authors.affiliation: Forma Therapeutics Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.affiliation: Pharmaron Beijing Co. Ltd, 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Xiongcai
authors.initials: X
authors.lastname: Liu
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Ly
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
authors.affiliation: Forma Therapeutics Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Reynolds
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Skelton
authors.affiliation: Forma Therapeutics Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Chase C
authors.initials: CC
authors.lastname: Smith
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Tay
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.affiliation: Forma Therapeutics Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Pharmaron Beijing Co. Ltd, 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Guiling
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Forma Therapeutics Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Xiaozhang
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry* / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008819:Mice, Nude; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014183:Transplantation, Heterologous; D014867:Water / Q000737:chemistry
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014867:Water; D051544:Cytochrome P-450 CYP3A; D054409:Nicotinamide Phosphoribosyltransferase; C030986:pyrimidine
keywords: Aqueous solubility; CYP TDI; Cytochrome P450 time-dependent inhibition; NAMPT; Nicotinamide phosphoribosyltransferase; Tumor metabolism