Novel 1,2,4-oxadiazoles and 1,2,4-thiadiazoles as dual 5-lipoxygenase and cyclooxygenase inhibitors

P C Unangst; G P Shrum; D T Connor; R D Dyer; D J Schrier

doi:10.1021/jm00098a015

Novel 1,2,4-oxadiazoles and 1,2,4-thiadiazoles as dual 5-lipoxygenase and cyclooxygenase inhibitors

J Med Chem. 1992 Oct 2;35(20):3691-8. doi: 10.1021/jm00098a015.

Authors

P C Unangst¹, G P Shrum, D T Connor, R D Dyer, D J Schrier

Affiliation

¹ Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.

PMID: 1433181
DOI: 10.1021/jm00098a015

Abstract

A series of 1,2,4-oxadiazoles and 1,2,4-thiadiazoles containing a 2,6-di-tert-butylphenol substituent were prepared and evaluated as dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia (RBL-1) cells. Several of these compounds show oral efficacy in the rat carrageenan footpad edema (CFE) and mycobacterium footpad edema (MFE) antiinflammatory models, without concomitant gastric ulceration. Structure-activity relationships are discussed. The best compounds (ID40 values in MFE of 3-8 mg/kg po) contain guanidine-derived substituents on the heterocyclic ring.

MeSH terms

Animals
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Cyclooxygenase Inhibitors / chemical synthesis*
Cyclooxygenase Inhibitors / pharmacology
Enzyme Inhibitors / chemical synthesis*
Lipoxygenase Inhibitors*
Male
Oxadiazoles / chemical synthesis*
Oxadiazoles / pharmacology
Rats
Rats, Wistar
Structure-Activity Relationship
Thiadiazoles / chemical synthesis*
Thiadiazoles / pharmacology
Tumor Cells, Cultured / drug effects
Tumor Cells, Cultured / metabolism

Substances

Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Lipoxygenase Inhibitors
Oxadiazoles
Thiadiazoles