title: Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
abstract: Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50 = 11 nM; PC-3 antiproliferative IC50 = 36 nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50 = 10nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined.
authors.affiliation: Genentech Inc, 1 DNA Way, South San Francisco, California 94080, USA. dragovich.peter@gene.com
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Bair
authors.forename: Timm
authors.initials: T
authors.lastname: Baumeister
authors.forename: Yen-Ching
authors.initials: YC
authors.lastname: Ho
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.forename: Xiongcai
authors.initials: X
authors.lastname: Liu
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Liu
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
authors.forename: Jason
authors.initials: J
authors.lastname: Oeh
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Nicholas
authors.initials: N
authors.lastname: Skelton
authors.forename: Leslie
authors.initials: L
authors.lastname: Wang
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Hongxing
authors.initials: H
authors.lastname: Wu
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
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D011725:Pyridines; D014508:Urea; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: Aqueous solubility; NAMPT; Nicotinamide phosphoribosyltransferase; Tumor metabolism; X-ray crystal structure