Abstract
The 4-hydroxypiperidine substituent was found to confer high p38 selectivity devoid of COX-1 affinity, when attached to a series of pyridinyl substituted heterocycles. Pyridinyloxazole 11 showed a promising in vivo profile with bioavailability of 64% and ED50 in rat collagen induced arthritis of 10 mg/kg po bid. In contrast to pyridinylimidazoles such as SB 203580, 11 did not inhibit human cytochrome P450 isoenzymes.
MeSH terms
-
Animals
-
Enzyme Inhibitors / chemistry*
-
Enzyme Inhibitors / pharmacology*
-
Heterocyclic Compounds / chemistry*
-
Humans
-
Imidazoles / chemistry
-
Imidazoles / pharmacology
-
Mitogen-Activated Protein Kinases / antagonists & inhibitors*
-
Piperidines / chemistry*
-
Pyridines / chemistry
-
Pyridines / pharmacology
-
Rats
-
Structure-Activity Relationship
-
p38 Mitogen-Activated Protein Kinases
Substances
-
Enzyme Inhibitors
-
Heterocyclic Compounds
-
Imidazoles
-
Piperidines
-
Pyridines
-
Mitogen-Activated Protein Kinases
-
p38 Mitogen-Activated Protein Kinases
-
SB 203580