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Substituted Isoxazoles as Potent Inhibitors of p38 MAP Kinase
Author(s) -
Laufer Stefan A.,
Margutti Simona,
Fritz Martina D.
Publication year - 2006
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200500025
Subject(s) - isoxazole , p38 mitogen activated protein kinases , chemistry , kinase , imidazole , mitogen activated protein kinase , cytochrome p450 , enzyme , in vitro , protein kinase a , potency , ring (chemistry) , stereochemistry , pharmacology , biochemistry , biology , organic chemistry
In a continuous effort to develop improved p38 MAP (mitogen‐activated protein) kinase inhibitors, we focused our attention on the suitability of the isoxazole ring as a bioisosteric replacement for the imidazole ring of SB‐203580. 3,4‐ and 4,5‐disubstituted as well as 3,4,5‐trisubstituted isoxazole derivatives were synthesized. These compounds were tested in an in vitro enzyme‐linked immunosorbent assay of isolated p38 MAP kinase and for inhibitory potency against cytochrome P450. Compound 4 a displays a highly promising profile for development as an anti‐inflammatory agent owing to its enhanced suppression of cytokine release, decreased affinity for cytochrome P450 and a twofold decrease in IC 50 toward isolated p38 MAP kinase.