Challenges and opportunities for developing selective carbonic anhydrase inhibitors and activators for vertebrate
1Neurofarba Department, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino (FI), Italy.
The Enzymes
|July 22, 2026
Summary
Developing selective carbonic anhydrase inhibitors is crucial for treating diseases with fewer side effects. New chemotypes like coumarins show promise for isoform- and class-selective inhibition, advancing therapeutic applications.
Area of Science:
- Biochemistry
- Pharmacology
- Medicinal Chemistry
Background:
- Carbonic anhydrases (CAs) are vital enzymes with 12 active mammalian isoforms.
- Traditional CA inhibitors (e.g., sulfonamides) are effective but cause side effects.
- Developing isoform-selective inhibitors is essential for targeted therapies.
Purpose of the Study:
- To review strategies for developing selective carbonic anhydrase inhibitors.
- To highlight novel chemotypes and their potential therapeutic applications.
- To discuss challenges in developing microbial-selective and activators for CAs.
Main Methods:
- Review of existing literature on carbonic anhydrase inhibitors.
- Analysis of structure-activity relationships for novel chemotypes (e.g., coumarins, boron-containing compounds).
- Evaluation of selectivity profiles (isoform, class, microbial vs. vertebrate).
Main Results:
- The 'tail approach' and new chemotypes (coumarins, boron/selenium compounds) yield selective inhibitors.
- SLC-0111 is a successful example of a tumor-associated CA IX and XII inhibitor.
- Coumarins exhibit class-selectivity for α- and η-CAs.
- Selective activators for mammalian CAs are currently unavailable.
Conclusions:
- Novel inhibitors offer improved therapeutic potential with reduced side effects.
- Targeting specific CA isoforms and classes presents opportunities for new treatments.
- Further research into selective CA modulators could unlock innovative pharmacological applications.
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