Synthesis, structure-activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 1. Thiazolone and oxazolone series

Y Song; D T Connor; R Doubleday; R J Sorenson; A D Sercel; P C Unangst; B D Roth; R B Gilbertsen; K Chan; D J Schrier; A Guglietta; D A Bornemeier; R D Dyer

doi:10.1021/jm9805081

Synthesis, structure-activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 1. Thiazolone and oxazolone series

J Med Chem. 1999 Apr 8;42(7):1151-60. doi: 10.1021/jm9805081.

Authors

Y Song¹, D T Connor, R Doubleday, R J Sorenson, A D Sercel, P C Unangst, B D Roth, R B Gilbertsen, K Chan, D J Schrier, A Guglietta, D A Bornemeier, R D Dyer

Affiliation

¹ Departments of Chemistry, Biochemistry, and Immunopathology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.

PMID: 10197959
DOI: 10.1021/jm9805081

Abstract

Selective cyclooxygenase-2 (COX-2) inhibitors have been shown to be potent antiinflammatory agents with fewer side effects than currently marketed nonsteroidal antiinflammatory drugs (NSAIDs). Initial mass screening and subsequent structure-activity relationship (SAR) studies have identified 4b (PD138387) as the most potent and selective COX-2 inhibitor within the thiazolone and oxazolone series of di-tert-butylphenols. Compound 4b has an IC50 of 1.7 microM against recombinant human COX-2 and inhibited COX-2 activity in the J774A.1 cell line with an IC50 of 0.17 microM. It was inactive against purified ovine COX-1 at 100 microM and did not inhibit COX-1 activity in platelets at 20 microM. Compound 4b was also orally active in vivo with an ED40 of 16 mg/kg in the carrageenan footpad edema (CFE) assay and caused no gastrointestinal (GI) damage in rats at the dose of 100 mg/kg but inhibited gastric prostaglandin E2 (PGE2) production in rats' gastric mucosa by 33% following a dose of 100 mg/kg. The SAR studies of this chemical series revealed that the potency and selectivity are very sensitive to minor structural changes. A simple isosteric replacement led to the reversal of selectivity.

MeSH terms

Administration, Oral
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Anti-Inflammatory Agents, Non-Steroidal / toxicity
Carrageenan / toxicity
Cell Line
Cyclooxygenase 1
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors / chemical synthesis*
Cyclooxygenase Inhibitors / chemistry
Cyclooxygenase Inhibitors / pharmacology
Cyclooxygenase Inhibitors / toxicity
Dinoprostone / antagonists & inhibitors
Edema / chemically induced
Edema / drug therapy
Gastric Mucosa / drug effects
Gastric Mucosa / metabolism
Humans
Hyperalgesia / drug therapy
Isoenzymes / metabolism*
Male
Membrane Proteins
Mice
Oxazoles / chemical synthesis*
Oxazoles / chemistry
Oxazoles / pharmacology
Oxazoles / toxicity
Phenols / chemical synthesis*
Phenols / chemistry
Phenols / pharmacology
Phenols / toxicity
Prostaglandin-Endoperoxide Synthases / metabolism*
Rats
Rats, Sprague-Dawley
Stomach Ulcer / chemically induced
Stomach Ulcer / pathology
Structure-Activity Relationship
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / pharmacology
Thiazoles / toxicity

Substances

Anti-Inflammatory Agents, Non-Steroidal
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Isoenzymes
Membrane Proteins
Oxazoles
PD 138387
Phenols
Thiazoles
Carrageenan
Cyclooxygenase 1
Cyclooxygenase 2
PTGS1 protein, human
PTGS2 protein, human
Prostaglandin-Endoperoxide Synthases
Ptgs1 protein, mouse
Ptgs1 protein, rat
Dinoprostone