Polypharmacology of carbonic anhydrase inhibitors and activators

Carbonic anhydrases (CAs) are enzymes involved in many physiologic and pathological processes connected with a diversity of conditions. Many of their inhibitors are used clinically for the management of glaucoma, epilepsy, obesity, and cancer. Some of these compounds also show significant polypharmacological effects. CA activators (CAAs) are not in clinical use.

PubMed and ScienceDirect databases were searched for articles published over the past 20 years. Several antiepileptics (topiramate, zonisamide, lacosamide, and levetiracetam), some atypical antipsychotics (sulpiride, veralipride), celecoxib, polmacoxib, pazopanib, the antiulcer agent famotidine, and compounds in clinical trials (epacadostat and PCI-27483) as antitumor agents significantly inhibit several CA isoforms of the 15 human ones, apart their action on several other targets. The possible role of CA inhibition in the therapeutic effects of these drugs, their side effects, and the possibility to use this information for drug design are discussed. CAAs belonging to a variety of aminergic classes (histaminergic, dopaminergic, and serotoninergic) are also discussed.

Polypharmacology involving CA inhibitors/CAAs is understood from the chemical, structural, and pharmacological viewpoints. The many other drug targets with which these modulators of activity interact allow for de novo design of such agents for the management of multifactorial conditions in need of innovative drugs.