title: Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
abstract: Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained.
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Xiaozhang
authors.initials: X
authors.lastname: Zheng
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Bair
authors.forename: Paul
authors.initials: P
authors.lastname: Bauer
authors.forename: Timm
authors.initials: T
authors.lastname: Baumeister
authors.forename: Krista K
authors.initials: KK
authors.lastname: Bowman
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: Yezhen
authors.initials: Y
authors.lastname: Feng
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: Hong
authors.initials: H
authors.lastname: Li
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: Justin
authors.initials: J
authors.lastname: Ly
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
authors.forename: Jason
authors.initials: J
authors.lastname: Oeh
authors.forename: Angela
authors.initials: A
authors.lastname: Oh
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Reynolds
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
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: Jarrod
authors.initials: J
authors.lastname: Tremayne
authors.forename: Leslie
authors.initials: L
authors.lastname: Wang
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Wang
authors.forename: Hongxing
authors.initials: H
authors.lastname: Wu
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Wu
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.forename: Guangxing
authors.initials: G
authors.lastname: Yang
authors.forename: Po-wai
authors.initials: PW
authors.lastname: Yuen
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D014183:Transplantation, Heterologous
chemical_list: D000577:Amides; D002264:Carboxylic Acids; D016207:Cytokines; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D013450:Sulfones; C447480:pyrazolo(3,4-b)pyridine; D009243:NAD; D009536:Niacinamide; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: Nicotinamide phosphoribosyltransferase (NAMPT); Tumor metabolism; X-ray crystal structure