Abstract
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.
MeSH terms
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Animals
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Anti-Inflammatory Agents
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Cyclooxygenase Inhibitors / chemical synthesis*
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Cyclooxygenase Inhibitors / chemistry
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Cyclooxygenase Inhibitors / pharmacology
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Lipoxygenase Inhibitors
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Male
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Oxadiazoles / chemical synthesis*
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Oxadiazoles / chemistry
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Oxadiazoles / pharmacology
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Rats
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Rats, Wistar
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Thiadiazoles / chemical synthesis*
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Thiadiazoles / chemistry
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Thiadiazoles / pharmacology
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Triazoles / chemical synthesis*
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Triazoles / chemistry
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Triazoles / pharmacology
Substances
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Anti-Inflammatory Agents
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclooxygenase Inhibitors
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Imidazoles
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Lipoxygenase Inhibitors
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Oxadiazoles
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Thiadiazoles
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Triazoles
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CI 986