Identification of isothiazole-4-carboxamidines derivatives as a novel class of allosteric MEK1 inhibitors.
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.
El Abdellaoui
Hassan
H
Drug Discovery, Valeant Pharmaceutical Research and Development, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA. HAbdellaoui@Cox.net
Varaprasad
Chamakura V N S
CV
Barawkar
Dinesh
D
Chakravarty
Subrata
S
Maderna
Andreas
A
Tam
Robert
R
Chen
Huanming
H
Allan
Matt
M
Wu
Jim Z
JZ
Appleby
Todd
T
Yan
Shunqi
S
Zhang
Weijian
W
Lang
Stanley
S
Yao
Nanhua
N
Hamatake
Robert
R
Hong
Zhi
Z
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
D000578:Amidines; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2