title: Identification of isothiazole-4-carboxamidines derivatives as a novel class of allosteric MEK1 inhibitors.
abstract: The development of potent, orally bioavailable, and selective series of 5-amino-3-hydroxy-N(1-hydroxypropane-2-yl)isothiazole-4-carboxamidine inhibitors of MEK1 and MEK-2 kinase is described. Optimization of the carboxamidine and the phenoxyaniline group led to the identification of 55 which gave good potency as in vitro MEK1 inhibitors, and good oral exposure in rat.
authors.affiliation: Drug Discovery, Valeant Pharmaceutical Research and Development, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA. HAbdellaoui@Cox.net
authors.forename: Hassan
authors.initials: H
authors.lastname: El Abdellaoui
authors.forename: Chamakura V N S
authors.initials: CV
authors.lastname: Varaprasad
authors.forename: Dinesh
authors.initials: D
authors.lastname: Barawkar
authors.forename: Subrata
authors.initials: S
authors.lastname: Chakravarty
authors.forename: Andreas
authors.initials: A
authors.lastname: Maderna
authors.forename: Robert
authors.initials: R
authors.lastname: Tam
authors.forename: Huanming
authors.initials: H
authors.lastname: Chen
authors.forename: Matt
authors.initials: M
authors.lastname: Allan
authors.forename: Jim Z
authors.initials: JZ
authors.lastname: Wu
authors.forename: Todd
authors.initials: T
authors.lastname: Appleby
authors.forename: Shunqi
authors.initials: S
authors.lastname: Yan
authors.forename: Weijian
authors.initials: W
authors.lastname: Zhang
authors.forename: Stanley
authors.initials: S
authors.lastname: Lang
authors.forename: Nanhua
authors.initials: N
authors.lastname: Yao
authors.forename: Robert
authors.initials: R
authors.lastname: Hamatake
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
mesh_terms: D000494:Allosteric Regulation; D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D051381:Rats
chemical_list: D000578:Amidines; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2