title: Tetrazolone as an acid bioisostere: application to marketed drugs containing a carboxylic acid.
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 AT1antagonist (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.
authors.affiliation: Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. mattduncton@yahoo.com mduncton@rigel.com.
authors.forename: Matthew A J
authors.initials: MA
authors.lastname: Duncton
authors.affiliation: Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. mattduncton@yahoo.com mduncton@rigel.com.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Murray
authors.affiliation: Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. mattduncton@yahoo.com mduncton@rigel.com.
authors.forename: Gary
authors.initials: G
authors.lastname: Park
authors.affiliation: Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. mattduncton@yahoo.com mduncton@rigel.com.
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000077610:Bexarotene; D001798:Blood Proteins / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006207:Half-Life; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects; D051381:Rats; D047490:Retinoid X Receptor alpha / Q000819:agonists; D000077333:Telmisartan; D013764:Tetrahydronaphthalenes / Q000737:chemistry* / Q000494:pharmacology; D013777:Tetrazoles / Q000737:chemistry*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001565:Benzoates; D001798:Blood Proteins; D002264:Carboxylic Acids; D016861:Cyclooxygenase Inhibitors; D047490:Retinoid X Receptor alpha; D013764:Tetrahydronaphthalenes; D013777:Tetrazoles; D000077610:Bexarotene; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D000077333:Telmisartan