PMID: 3746810Sep 1, 1986Paper

Structure-activity relationships of (arylalkyl)imidazole anticonvulsants: comparison of the (fluorenylalkyl)imidazoles with nafimidone and denzimol

Journal of Medicinal Chemistry
D W RobertsonR C Rathbun

Abstract

A recently discovered and structurally distinct class of antiepileptic drugs is the (arylalkyl)imidazoles. Two independently discovered representatives of this class, denzimol (alpha-[4-(2-phenylethyl)phenyl]-1H-imidazole-1-ethanol) and nafimidone (2-(1H-imidazol-1-yl)-1-(2-naphthalenyl)ethanone), are undergoing clinical evaluation. Our structure-activity relationship (SAR) studies revealed that in addition to the naphthalenyl and phenethylphenyl aryl moieties of nafimidone and denzimol, respectively, fluorenyl, benzo[b]thienyl, and benzofuranyl aryl groups provided several highly active (arylalkyl)imidazole anticonvulsants. These structurally diverse aryl moieties, and comparable anticonvulsant activities, lend credence to the hypothesis that the pharmacophore of this class of anticonvulsants is the alkylimidazole portion of the molecule, with the lipophilic aryl portion enabling penetration of the blood-brain barrier. We focused our SAR studies on the (fluorenylalkyl)imidazole series. A representative compound from this series is 1-(9H-fluoren-2-yl)-2-(1H-imidazol-1-yl)ethanone. This agent was twice as potent as nafimidone in inhibiting maximal electroshock seizures in mice (po ED50's = 25 and 56 mg/kg, respectively) and cons...Continue Reading

Citations

Jan 1, 1988·Epilepsy Research·T E Albertson, W F Walby
Nov 1, 1988·Epilepsia·D W RobertsonJ D Leander
Mar 7, 2003·Applied and Environmental Microbiology·Annett MikolaschFrieder Schauer
Jan 31, 2016·European Journal of Medicinal Chemistry·Adile AyatiAlireza Foroumadi
Apr 1, 1995·Journal of Pharmaceutical Sciences·D D ErolM Ertan
Oct 14, 2018·Pharmacological Reports : PR·Suat SariSevim Dalkara
Mar 15, 2013·Dalton Transactions : an International Journal of Inorganic Chemistry·Jianfang ChaiStephen A Miller
Oct 27, 2018·European Journal of Medicinal Chemistry·Subhajit MakarSushil K Singh
Aug 15, 2021·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Mehdi ValipourHamid Irannejad
Nov 9, 2019·Journal of Medicinal Chemistry·John G WisePia D Vogel

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