title: Discovery of potent and efficacious urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with reduced CYP2C9 inhibition properties.
abstract: Potent, reversible inhibition of the cytochrome P450 CYP2C9 isoform was observed in a series of urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. This unwanted property was successfully removed from the described inhibitors through a combination of structure-based design and medicinal chemistry activities. An optimized compound which did not inhibit CYP2C9 exhibited potent anti-NAMPT activity (17; BC NAMPT IC50=3 nM; A2780 antiproliferative IC50=70 nM), good mouse PK properties, and was efficacious in an A2780 mouse xenograft model. The crystal structure of this compound in complex with the NAMPT protein is also described.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Gunzner-Toste
authors.forename: Guiling
authors.initials: G
authors.lastname: Zhao
authors.forename: Paul
authors.initials: P
authors.lastname: Bauer
authors.forename: Timm
authors.initials: T
authors.lastname: Baumeister
authors.forename: Alexandre J
authors.initials: AJ
authors.lastname: Buckmelter
authors.forename: Maureen
authors.initials: M
authors.lastname: Caligiuri
authors.forename: Karl H
authors.initials: KH
authors.lastname: Clodfelter
authors.forename: Bang
authors.initials: B
authors.lastname: Fu
authors.forename: Bingsong
authors.initials: B
authors.lastname: Han
authors.forename: Yen-Ching
authors.initials: YC
authors.lastname: Ho
authors.forename: Nikolai
authors.initials: N
authors.lastname: Kley
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Liang
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.forename: Sophie
authors.initials: S
authors.lastname: Mukadam
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
authors.forename: Angela
authors.initials: A
authors.lastname: Oh
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Reynolds
authors.forename: Geeta
authors.initials: G
authors.lastname: Sharma
authors.forename: Nicholas
authors.initials: N
authors.lastname: Skelton
authors.forename: Chase C
authors.initials: CC
authors.lastname: Smith
authors.forename: Jasleen
authors.initials: J
authors.lastname: Sodhi
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.forename: Po-wai
authors.initials: PW
authors.lastname: Yuen
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaozhang
authors.initials: X
authors.lastname: Zheng
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Bair
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D014508:Urea; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D054409:Nicotinamide Phosphoribosyltransferase