title: Indanesulfonamides as carbonic anhydrase inhibitors and anticonvulsant agents: structure-activity relationship and pharmacological evaluation.
abstract: A small library of indanesulfonamides was screened for the inhibition of the human carbonic anhydrase (CA, EC 4.2.1.1) isoforms involved in neuronal excitation, that is, isoforms VII, XII and XIV. These CA isoforms are becoming interesting target for the design of agents useful for the treatment of epilepsy. The inhibition pattern of these indanesulfonamide compounds towards these three isoforms was excellent, with many nanomolar inhibitors detected (K(I)s in the range of 0.78-10 nM against hCA VII; 0.32-56 nM against hCA XII, and 0.47-1030 nM against hCA XIV, respectively). The maximal electroshock seizure (MES) test performed on mice showed a good anticonvulsant activity for some compounds which protected the mice against convulsions in the 50-62.5% range at a dose of 50 mg/kg. In parallel, the blood-brain barrier passive permeation of these sulfonamides was also estimated by using a computational approach.
authors.affiliation: Drug Design and Discovery Center, FUNDP, University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium. anne.thiry@fundp.ac.be
authors.forename: Anne
authors.initials: A
authors.lastname: Thiry
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rolin
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Aurélie
authors.initials: A
authors.lastname: Frankart
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000187:drug effects* / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000502:physiology; D003198:Computer Simulation; D004597:Electroshock; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D008956:Models, Chemical; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015203:Reproducibility of Results; D012640:Seizures / Q000517:prevention & control*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; D002256:Carbonic Anhydrases