Discovery of Subnanomolar and Highly Selective Carbonic Anhydrase II Inhibitors Featuring L-Shaped Scaffolds via Active-Site-Matched Fragment Growing

  • J Med Chem. 2026 Jun 25;69(12):14461-14491. doi: 10.1021/acs.jmedchem.6c00308.
Yitong Wang  1 ,  Alessio Nocentini  2 ,  Marta Ferraroni  3 ,  Andrea Angeli  2 ,  Xin Wang  1 ,  Zhongyu Liu  1 ,  Mengbi Guo  1 ,  Cheng Peng  4 ,  Bin Lin  1 ,  Zhuang Hou  1 ,  Yang Liu  1 ,  Claudiu T Supuran  2 ,  Chun Guo  1
Affiliations
  • 1. Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2. Department of NEUROFARBA -Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino, Firenze 50019, Italy.
  • 3. Department of Chemistry "Ugo Schiff" (DICUS), University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, Florence 50019, Italy.
  • 4. Department of Ophthalmology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110016, China.
PMID: 42290333 DOI: 10.1021/acs.jmedchem.6c00308
Abstract

Glaucoma is a leading cause of irreversible blindness worldwide, and lowering intraocular pressure (IOP) remains the only proven method to delay progression. While topical Carbonic Anhydrase (CA) inhibitors are established treatments, more potent and selective agents are needed. We report a series of subnanomolar and highly selective human Carbonic Anhydrase (hCA) II inhibitors developed through a multistage fragment growth strategy. By incrementally expanding a weakly bound sulfanilamide anchor to precisely complement the enzyme's topology, we achieved a remarkable 15,000-fold increase in potency, resulting in subnanomolar inhibition and exceptional selectivity. High-resolution X-ray crystallography revealed a distinct L-shaped configuration, effectively occupying the entire active site and establishing unique interactions with a peripheral α-helix. In rabbit glaucoma models, these inhibitors demonstrated superior IOP-lowering activity. Furthermore, the inhibitors exhibited exceptional metabolic stability, minimal ocular toxicity, and favorable safety profiles. These results demonstrate multistage fragment growth as a robust strategy for designing next-generation glaucoma therapeutics.

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