Synthesis and Evaluation of Carbonic Anhydrase Inhibitors with Carbon Monoxide Releasing Properties for the Management of Rheumatoid Arthritis.

Abstract

Carbon monoxide (CO) is a gas endogenously produced in humans, reported to exhibit anti-inflammatory and cytoprotective effects at low concentration. In this context, CO releasing molecules (CORMs) are attracting enormous interest. Herein, we report a series of small-molecule hybrids consisting of a carbonic anhydrase (CA; EC 4.2.1.1) inhibitor linked to a CORM tail section (CAI-CORMs). All compounds were screened in vitro for their inhibition activity against the human (h) CA I, II, IV, IX, and XII isoforms. On selected CAI-CORM hybrids, the CO releasing properties were evaluated, along with their pain-relieving effect, in a model of rheumatoid arthritis. One CAI-CORM hybrid (5b) induced a higher pain-relieving effect compared to the one exerted by the single administration of CAI (5a) and CORM (15b) fragments, shedding light on the possibility to enhance the pain relief effect of CA inhibitors inserting a CO releasing moiety on the same molecular scaffold.

• Authors: Emanuela Berrino, Lisa Milazzo, Laura Micheli, Daniela Vullo, Andrea Angeli, Murat Bozdag, Alessio Nocentini, Marta Menicatti, Gianluca Bartolucci, Lorenzo di Cesare Mannelli, Carla Ghelardini, Claudiu T Supuran, Fabrizio Carta
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 15 Pg. 7233-7249 (08 08 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 31287314 (Publication Type: Journal Article)

Chemical References

• Antirheumatic Agents
• Carbonic Anhydrase Inhibitors
• Carbon Monoxide

Topics

• Animals
• Antirheumatic Agents (chemical synthesis, therapeutic use)
• Arthritis, Rheumatoid (drug therapy, metabolism)
• Carbon Monoxide (metabolism)
• Carbonic Anhydrase Inhibitors (chemical synthesis, therapeutic use)
• Disease Management
• Humans
• Rats
• Rats, Sprague-Dawley