Potent and selective pyrazolo[1,5-a]pyrimidine based inhibitors of B-Raf(V600E) kinase with favorable physicochemical and pharmacokinetic properties.

Li Ren, Ellen R Laird, Alex J Buckmelter, Victoria Dinkel, Susan L Gloor, Jonas Grina, Brad Newhouse, Kevin Rasor, Gregg Hastings, Stefan N Gradl, Joachim Rudolph

Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, USA. li.ren@arraybiopharma.com

Bioorganic & medicinal chemistry letters 2012 Jan 15

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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. Copyright © 2011 Elsevier Ltd. All rights reserved.

Citation

Li Ren, Ellen R Laird, Alex J Buckmelter, Victoria Dinkel, Susan L Gloor, Jonas Grina, Brad Newhouse, Kevin Rasor, Gregg Hastings, Stefan N Gradl, Joachim Rudolph. Potent and selective pyrazolo[1,5-a]pyrimidine based inhibitors of B-Raf(V600E) kinase with favorable physicochemical and pharmacokinetic properties. Bioorganic & medicinal chemistry letters. 2012 Jan 15;22(2):1165-8