SAR of 4-hydroxypiperidine and hydroxyalkyl substituted heterocycles as novel p38 map kinase inhibitors

L Revesz; F E Di Padova; T Buhl; R Feifel; H Gram; P Hiestand; U Manning; A G Zimmerlin

doi:10.1016/s0960-894x(00)00200-6

SAR of 4-hydroxypiperidine and hydroxyalkyl substituted heterocycles as novel p38 map kinase inhibitors

Bioorg Med Chem Lett. 2000 Jun 5;10(11):1261-4. doi: 10.1016/s0960-894x(00)00200-6.

Authors

L Revesz¹, F E Di Padova, T Buhl, R Feifel, H Gram, P Hiestand, U Manning, A G Zimmerlin

Affiliation

¹ Arthritis and Bone Research, Novartis Pharma AG, Switzerland. laszlo.revesz@pharma.novartis.com

PMID: 10866395
DOI: 10.1016/s0960-894x(00)00200-6

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