title: Potent and selective pyrazolo[1,5-a]pyrimidine based inhibitors of B-Raf(V600E) kinase with favorable physicochemical and pharmacokinetic properties.
abstract: Herein we describe a novel series of ATP competitive B-Raf inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with improved physicochemical and pharmacokinetic properties.
authors.affiliation: Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, USA. li.ren@arraybiopharma.com
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Buckmelter
authors.forename: Victoria
authors.initials: V
authors.lastname: Dinkel
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gloor
authors.forename: Jonas
authors.initials: J
authors.lastname: Grina
authors.forename: Brad
authors.initials: B
authors.lastname: Newhouse
authors.forename: Kevin
authors.initials: K
authors.lastname: Rasor
authors.forename: Gregg
authors.initials: G
authors.lastname: Hastings
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Gradl
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C527752:pyrazolo(1,5-a)pyrimidine; D048493:Proto-Oncogene Proteins B-raf