title: Novel pyrazolopyrimidines as highly potent B-Raf inhibitors.
abstract: A novel series of pyrazolo[1,5-a]pyrimidines bearing a 3-hydroxyphenyl group at C(3) and substituted tropanes at C(7) have been identified as potent B-Raf inhibitors. Exploration of alternative functional groups as a replacement for the C(3) phenol demonstrated indazole to be an effective isostere. Several compounds possessing substituted indazole residues, such as 4e, 4p, and 4r, potently inhibited cell proliferation at submicromolar concentrations in the A375 and WM266 cell lines, and the latter two compounds also exhibited good therapeutic indices in cells.
authors.affiliation: Chemical Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA. digranm@pfizer.com
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Di Grandi
authors.forename: Dan M
authors.initials: DM
authors.lastname: Berger
authors.forename: Darrin W
authors.initials: DW
authors.lastname: Hopper
authors.forename: Chunchun
authors.initials: C
authors.lastname: Zhang
authors.forename: Minu
authors.initials: M
authors.lastname: Dutia
authors.forename: Alejandro L
authors.initials: AL
authors.lastname: Dunnick
authors.forename: Nancy
authors.initials: N
authors.lastname: Torres
authors.forename: Jeremy I
authors.initials: JI
authors.lastname: Levin
authors.forename: George
authors.initials: G
authors.lastname: Diamantidis
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Zapf
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Bloom
authors.forename: YongBo
authors.initials: Y
authors.lastname: Hu
authors.forename: Dennis
authors.initials: D
authors.lastname: Powell
authors.forename: Donald
authors.initials: D
authors.lastname: Wojciechowicz
authors.forename: Karen
authors.initials: K
authors.lastname: Collins
authors.forename: Eileen
authors.initials: E
authors.lastname: Frommer
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; C447480:pyrazolo(3,4-b)pyridine; D048493:Proto-Oncogene Proteins B-raf