Challenges and opportunities for developing selective carbonic anhydrase inhibitors and activators for vertebrate isoforms.
Supuran Claudiu T CT
Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors of the sulfonamide/sulfamate type, such as acetazolamide, thiazides/high-ceiling diuretics, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, antiepileptics (sulthiame, topiramate, zonisamide), or non-steroidal anti-inflammatory agents such as celecoxib and polmacoxib, are effective inhibitors of most CA isoforms present in vertebrates but their clinical use in various pathologies is associated with side effects. Significant efforts were done in the last decades for developing isoform-selective inhibitors for all 12 catalytically active mammalian isoforms, with important results being obtained by using the tail approach or by the discovery of new inhibitory chemotypes, such as the coumarins and their derivatives, the boron/selenium-containing compounds, etc. SLC-0111, an antitumor sulfonamide in clinical development is an example of a successful strategy emerged by using the tail approach, this compound being a selective inhibitor of the tumor-associated isoforms CA IX and XII. Coumarins, sulfocoumarins and some boron-containing compounds show significant levels of isoform-selective inhibition against many CA isoforms too. Few compounds, on the other hand, show selectivity for inhibiting microbial over vertebrate isoforms, which is a considerable challenge for developing anti-infectives based on CA inhibitors. At the moment, only coumarins act as class-selective inhibitors for α- and η-CAs, not inhibiting significantly other CA classes (β-, γ-, δ-, ζ-, θ- and ι-CAs). Selective CA activators for the mammalian isoforms are not available yet, although they might lead to relevant pharmacological applications for the management of neurodegenerations, emotional memory disorders, obsessive-compulsive disorders, phobias, post-traumatic stress. Finding more effective isoform-selective and more importantly, class-selective modulators of activity for vertebrate CAs might afford opportunities for innovative therapeutic/pharmacological applications.