title: Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline.
abstract: The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent in xenograft models.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. adrians@amgen.com
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Smith
authors.forename: Frenel F
authors.initials: FF
authors.lastname: DeMorin
authors.forename: Nick A
authors.initials: NA
authors.lastname: Paras
authors.forename: Qi
authors.initials: Q
authors.lastname: Huang
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Petkus
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Doherty
authors.forename: Thomas
authors.initials: T
authors.lastname: Nixey
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kim
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Linda F
authors.initials: LF
authors.lastname: Epstein
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lee
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rose
authors.forename: Carol
authors.initials: C
authors.lastname: Babij
authors.forename: Manory
authors.initials: M
authors.lastname: Fernando
authors.forename: Kristen
authors.initials: K
authors.lastname: Hess
authors.forename: Quynh
authors.initials: Q
authors.lastname: Le
authors.forename: Pedro
authors.initials: P
authors.lastname: Beltran
authors.forename: Josette
authors.initials: J
authors.lastname: Carnahan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D055808:Drug Discovery; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D050505:Mutant Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013379:Substrate Specificity
chemical_list: D007546:Isoquinolines; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; C041545:1-aminoisoquinoline