title: Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors.
abstract: NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound 68, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested.
authors.affiliation: Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
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: 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, California 94080, United States.
authors.forename: Snahel
authors.initials: S
authors.lastname: Patel
authors.affiliation: Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.affiliation: Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Oeh
authors.affiliation: Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.affiliation: Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.affiliation: Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
authors.affiliation: Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Skelton
authors.affiliation: Pharmaron Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Rongbao
authors.initials: R
authors.lastname: Hua
authors.affiliation: Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jasleen
authors.initials: J
authors.lastname: Sodhi
authors.affiliation: Pharmaron Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Yunli
authors.initials: Y
authors.lastname: Wang
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, California 94080, United States.
authors.forename: Guiling
authors.initials: G
authors.lastname: Zhao
authors.affiliation: FORMA Therapeutics Inc. , 500 Arsenal Street, Watertown, Massachusetts 02472, United States.
authors.forename: Xiaozhang
authors.initials: X
authors.lastname: Zheng
authors.affiliation: FORMA Therapeutics Inc. , 500 Arsenal Street, Watertown, Massachusetts 02472, United States.
authors.forename: Yen-Ching
authors.initials: YC
authors.lastname: Ho
authors.affiliation: FORMA Therapeutics Inc. , 500 Arsenal Street, Watertown, Massachusetts 02472, United States.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Bair
authors.affiliation: Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism*; D065688:Cytochrome P-450 CYP2C9 Inhibitors / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D065688:Cytochrome P-450 CYP2C9 Inhibitors; D004791:Enzyme Inhibitors; D011725:Pyridines; D065729:Cytochrome P-450 CYP2C9; D054409:Nicotinamide Phosphoribosyltransferase