title: Design and Comparative Evaluation of the Anticonvulsant Profile, Carbonic-Anhydrate Inhibition and Teratogenicity of Novel Carbamate Derivatives of Branched Aliphatic Carboxylic Acids with 4-Aminobenzensulfonamide.
abstract: Epilepsy is one of the most common neurological diseases, with between 34 and 76 per 100,000 people developing epilepsy annually. Epilepsy therapy for the past 100+years is based on the use of antiepileptic drugs (AEDs). Despite the availability of more than twenty old and new AEDs, approximately 30% of patients with epilepsy are not seizure-free with the existing medications. In addition, the clinical use of the existing AEDs is restricted by their side-effects, including the teratogenicity associated with valproic acid that restricts its use in women of child-bearing age. Thus, there is an unmet clinical need to develop new, effective AEDs. In the present study, a novel class of carbamates incorporating phenethyl or branched aliphatic chains with 6-9 carbons in their side-chain, and 4-benzenesulfonamide-carbamate moieties were synthesized and evaluated for their anticonvulsant activity, teratogenicity and carbonic anhydrase (CA) inhibition. Three of the ten newly synthesized carbamates showed anticonvulsant activity in the maximal-electroshock (MES) and 6 Hz tests in rodents. In mice, 3-methyl-2-propylpentyl(4-sulfamoylphenyl)carbamate(1), 3-methyl-pentan-2-yl-(4-sulfamoylphenyl)carbamate (9) and 3-methylpentyl, (4-sulfamoylphenyl)carbamate (10) had ED50values of 136, 31 and 14 mg/kg (MES) and 74, 53, and 80 mg/kg (6 Hz), respectively. Compound (10) had rat-MES-ED50= 13 mg/kg and ED50of 59 mg/kg at the mouse-corneal-kindling test. These potent carbamates (1,9,10) induced neural tube defects only at doses markedly exceeding their anticonvuslnat-ED50values. None of these compounds were potent inhibitors of CA IV, but inhibited CA isoforms I, II and VII. The anticonvulsant properties of these compounds and particularly compound 10 make them potential candidates for further evaluation and development as new AEDs.
authors.affiliation: Faculty of Medicine, School of Pharmacy, Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Bibi
authors.affiliation: Faculty of Medicine, School of Pharmacy, Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Hafiz
authors.initials: H
authors.lastname: Mawasi
authors.affiliation: NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019, Florence, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Nocentini
authors.affiliation: NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019, Florence, Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Department of Pediatrics, The University of Texas at Austin Dell Medical School, Austin, TX, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Wlodarczyk
authors.affiliation: Department of Pediatrics, The University of Texas at Austin Dell Medical School, Austin, TX, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.affiliation: Faculty of Medicine, School of Pharmacy, Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel. bialer@md.huji.ac.il.|Affiliated with the David R. Bloom Center for Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel. bialer@md.huji.ac.il.
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D002219:Carbamates / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D002264:Carboxylic Acids / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D000077145:Sulfanilamide; D013424:Sulfanilamides / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D013723:Teratogens / Q000737:chemistry / Q000633:toxicity
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D002264:Carboxylic Acids; D013424:Sulfanilamides; D013723:Teratogens; D000077145:Sulfanilamide; D002256:Carbonic Anhydrases
keywords: 4-Aminobenzensulfonamides; Carbonic anhydrase inhibition; New antiepileptic drugs; Teratogenicity; Valproic acid