SAR of 4-hydroxypiperidine and hydroxyalkyl substituted heterocycles as novel p38 map kinase inhibitors.
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.
Revesz
L
L
Arthritis and Bone Research, Novartis Pharma AG, Switzerland. laszlo.revesz@pharma.novartis.com
Di Padova
F E
FE
Buhl
T
T
Feifel
R
R
Gram
H
H
Hiestand
P
P
Manning
U
U
Zimmerlin
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AG
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D007093:Imidazoles; D010880:Piperidines; D011725:Pyridines; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580