Abstract
Matched molecular pair analysis was used to evaluate the ability of a tetrazolone group to act as a bioisostere of a carboxylic acid. Compound 7, a tetrazolone of the anti-hypertensive drug, telmisartan 6, was shown to be a potent AT1 antagonist (Kb = 0.14 nM), with activity comparable to telmisartan itself (Kb = 0.44 nM). Additionally, compound 9, a tetrazolone congener of the marketed anti-cancer agent, bexarotene 8, was shown to be an agonist at the retinoid X receptor alpha (EC50 = 64 nM). Compounds containing a tetrazolone group showed similar microsomal stability and plasma protein binding to marketed acid counterparts, while also reducing the value for clog P. Furthermore, compound 7 displayed an improved rat pharmacokinetic profile cf. telmisartan 6. Taken together, the results demonstrate that a tetrazolone group may serve as a bioisostere for a carboxylic acid.
MeSH terms
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Angiotensin II Type 1 Receptor Blockers / chemistry
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Angiotensin II Type 1 Receptor Blockers / pharmacology*
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Benzimidazoles / chemistry*
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology
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Benzoates / chemistry*
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Benzoates / pharmacokinetics
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Benzoates / pharmacology
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Bexarotene
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Blood Proteins / metabolism
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Carboxylic Acids / chemistry
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Cyclooxygenase 1 / metabolism
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Cyclooxygenase Inhibitors / chemistry
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Cyclooxygenase Inhibitors / pharmacology
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Drug Evaluation, Preclinical / methods
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Half-Life
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Humans
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Microsomes, Liver / drug effects
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Rats
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Retinoid X Receptor alpha / agonists
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Telmisartan
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Tetrahydronaphthalenes / chemistry*
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Tetrahydronaphthalenes / pharmacology
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Tetrazoles / chemistry*
Substances
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Angiotensin II Type 1 Receptor Blockers
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Antineoplastic Agents
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Benzimidazoles
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Benzoates
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Blood Proteins
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Carboxylic Acids
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Cyclooxygenase Inhibitors
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Retinoid X Receptor alpha
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Tetrahydronaphthalenes
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Tetrazoles
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Bexarotene
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Cyclooxygenase 1
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PTGS1 protein, human
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Telmisartan