title: Hit to lead optimization of pyrazolo[1,5-a]pyrimidines as B-Raf kinase inhibitors.
abstract: Our continued effort towards optimization of the pyrazolo[1,5-a]pyrimidine scaffold as B-Raf kinase inhibitors is described. Structure guided design was utilized to introduce kinase hinge region interacting groups in the 2-position of the scaffold. This strategy led to the identification of lead compound 9 with enhanced enzyme and cellular potency, while maintaining good selectivity over a number of kinases.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. gopalsa@wyeth.com
authors.forename: Ariamala
authors.initials: A
authors.lastname: Gopalsamy
authors.forename: Greg
authors.initials: G
authors.lastname: Ciszewski
authors.forename: Mengxiao
authors.initials: M
authors.lastname: Shi
authors.forename: Dan
authors.initials: D
authors.lastname: Berger
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Hu
authors.forename: Frederick
authors.initials: F
authors.lastname: Lee
authors.forename: Larry
authors.initials: L
authors.lastname: Feldberg
authors.forename: Eileen
authors.initials: E
authors.lastname: Frommer
authors.forename: Steven
authors.initials: S
authors.lastname: Kim
authors.forename: Karen
authors.initials: K
authors.lastname: Collins
authors.forename: Donald
authors.initials: D
authors.lastname: Wojciechowicz
authors.forename: Robert
authors.initials: R
authors.lastname: Mallon
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C527752:pyrazolo(1,5-a)pyrimidine; D048493:Proto-Oncogene Proteins B-raf