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. 2. 1,3,4- and 1,2,4-thiadiazole series

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

doi:10.1021/jm980570y

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. 2. 1,3,4- and 1,2,4-thiadiazole series

J Med Chem. 1999 Apr 8;42(7):1161-9. doi: 10.1021/jm980570y.

Authors

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

Affiliation

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

PMID: 10197960
DOI: 10.1021/jm980570y

Abstract

Two isoforms of the cyclooxygenase (COX) enzyme have been identified: COX-1, which is expressed constitutively, and COX-2, which is induced in inflammation. Recently, it has been shown that selective COX-2 inhibitors have antiinflammatory activity and lack the GI side effects typically associated with NSAIDs. Initial mass screening and subsequent SAR studies have identified 6b (PD164387) as a potent, selective, and orally active COX-2 inhibitor. It had IC50 values of 0.14 and 100 microM against recombinant human COX-2 and purified ovine COX-1, respectively. It inhibited COX-2 activity in the J774A.1 cell line with an IC50 of 0.18 microM and inhibited COX-1 activity in platelets with an IC50 of 3.1 microM. The choline salt of compound 6b was also orally active in vivo with an ED40 of 7. 1 mg/kg in the carrageenan footpad edema (CFE) assay. In vivo studies in rats at a dose of 100 mg/kg showed that this compound inhibited gastric prostaglandin E2 (PGE2) production in gastric mucosa by 77% but caused minimal GI damage. SAR studies of this chemical series revealed that the potency and selectivity are very sensitive to minor structural changes.

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
Blood Platelets / drug effects
Blood Platelets / enzymology
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
In Vitro Techniques
Isoenzymes / metabolism*
Male
Membrane Proteins
Mice
Phenols / chemical synthesis*
Phenols / chemistry
Phenols / pharmacology
Phenols / toxicity
Prostaglandin-Endoperoxide Synthases / metabolism*
Rats
Rats, Sprague-Dawley
Recombinant Proteins / antagonists & inhibitors
Sheep
Stomach Ulcer / chemically induced
Stomach Ulcer / pathology
Structure-Activity Relationship
Thiadiazoles / chemical synthesis*
Thiadiazoles / chemistry
Thiadiazoles / pharmacology
Thiadiazoles / toxicity

Substances

Anti-Inflammatory Agents, Non-Steroidal
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Isoenzymes
Membrane Proteins
PD 164387
Phenols
Recombinant Proteins
Thiadiazoles
Carrageenan
Cyclooxygenase 1
Cyclooxygenase 2
PTGS1 protein, human
PTGS2 protein, human
Prostaglandin-Endoperoxide Synthases
Ptgs1 protein, mouse
Ptgs1 protein, rat
Dinoprostone