Anticonvulsant/antiepileptic carbonic anhydrase inhibitors: a patent review

An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. The International League Against Epilepsy classifies seizures in two broad categories: partial (localized to one cerebral hemisphere) and generalized (localized to both cerebral hemispheres). One indirect pathway for the treatment of epilepsy includes the inhibition of carbonic anhydrase (CA), thereby increasing CO(2) levels in the brain.

Carbonic anhydrases (EC 4.2.1.1) are ubiquitous metalloenzymes that catalyze the reversible hydration/dehydration of CO(2)/HCO(3)(-), respectively. CA inhibitors (CAIs) such as acetazolamide, methazolamide, topiramate, zonisamide, and sulthiame can reduce seizures through perturbation of the CO(2) equilibrium and/or the inhibition of ion channels. This review focuses on the mechanism of epilepsy, CA catalysis, and recent developments in the treatment of epilepsy using CAIs.

Based on the observed active-site binding interactions of CAIs in crystal structures and their respective inhibition constants, structure-activity relationships can be mapped. Various CAIs along with novel techniques to administer them have been patented in the last four years. However, epilepsy continues to be a path less traveled when it comes to CAIs. A major area of research must focus toward the design of isoform-specific inhibitors using analogs of existing CAIs.