title: Discovery of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1: optimization of kinase selectivity and pharmacokinetics.
abstract: The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer.
authors.affiliation: OSI Pharmaceuticals LLC, 1 Bioscience Park Drive, Farmingdale, NY 11735, USA. keith.hornberger@boehringer-ingelheim.com
authors.forename: Keith R
authors.initials: KR
authors.lastname: Hornberger
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Crew
authors.forename: Andrew
authors.initials: A
authors.lastname: Kleinberg
authors.forename: Lifu
authors.initials: L
authors.lastname: Ma
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mulvihill
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Wilde
authors.forename: Mark
authors.initials: M
authors.lastname: Albertella
authors.forename: Mark
authors.initials: M
authors.lastname: Bittner
authors.forename: Andrew
authors.initials: A
authors.lastname: Cooke
authors.forename: Salam
authors.initials: S
authors.lastname: Kadhim
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kahler
authors.forename: Paul
authors.initials: P
authors.lastname: Maresca
authors.forename: Earl
authors.initials: E
authors.lastname: May
authors.forename: Peter
authors.initials: P
authors.lastname: Meyn
authors.forename: Darlene
authors.initials: D
authors.lastname: Romashko
authors.forename: Brianna
authors.initials: B
authors.lastname: Tokar
authors.forename: Roy
authors.initials: R
authors.lastname: Turton
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D010770:Phosphotransferases / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000588:Amines; D004791:Enzyme Inhibitors; D005663:Furans; D020930:MAP Kinase Kinase Kinases; D010770:Phosphotransferases; D011725:Pyridines; D000099151:MAP Kinase Kinase Kinase 7
keywords: 7-Amino-furo[2,3-c]pyridine; Cancer; Inflammation; Inhibitors; TAK1