Design of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3,4-thiadiazoles, -1,3,4-oxadiazoles, and -1,2,4-triazoles as orally-active, nonulcerogenic antiinflammatory agents.
To discover dual inhibitors of 5-lipoxygenase (LO) and cyclooxygenase (CO) with improved pharmacokinetic properties, we have designed and synthesized series of 1,2,4-triazole, 1,3,4-oxadiazole, and 1,3,4-thiadiazole di-tert-butylphenol derivatives which exhibit a wide range of log P (2.3 to > 4) and pKa (5.5-12) values. From this work 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)- thione, choline salt (12a, CI-986) was found to be a potent inhibitor of 5-LO (IC50 = 2.8 microM) and CO (IC50 = 0.8 microM), orally active in rat models of inflammation and nonulcerogenic.
Mullican
M D
MD
Department of Medicinal Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Wilson
M W
MW
Connor
D T
DT
Kostlan
C R
CR
Schrier
D J
DJ
Dyer
R D
RD
D000818:Animals; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D008297:Male; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D010069:Oxadiazoles; D013830:Thiadiazoles; D014230:Triazoles; C080863:CI 986