Design and Synthesis of Novel Nonsteroidal Anti-Inflammatory Drugs and Carbonic Anhydrase Inhibitors Hybrids (NSAIDs-CAIs) for the Treatment of Rheumatoid Arthritis.

Abstract

We report the synthesis of a series of hybrid compounds incorporating 6- and 7-substituted coumarins (carbonic anhydrase, CA inhibitors) derivatized with clinically used NSAIDs (indomethacin, sulindac, ketoprofen, ibuprofen, diclofenac, ketorolac, etc., cyclooxygenase inhibitors) as agents for the management of rheumatoid arthritis (RA). Most compounds were effective in inhibiting the RA overexpressed hCA IX and XII, with KI values in the low nanomolar-subnanomolar ranges. The antihyperalgesic activity of such compounds was assessed by means of the paw-pressure and incapacitance tests using an in vivo RA model. Among all tested compounds, the 7-coumarine hybrid with ibuprofen showed potent and persistent antihyperalgesic effect up to 60 min after administration.

• Authors: Silvia Bua, Lorenzo Di Cesare Mannelli, Daniela Vullo, Carla Ghelardini, Gianluca Bartolucci, Andrea Scozzafava, Claudiu T Supuran, Fabrizio Carta
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 3 Pg. 1159-1170 (02 09 2017) ISSN: 1520-4804 [Electronic] United States
• PMID: 28075587 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Anti-Inflammatory Agents, Non-Steroidal
• Carbonic Anhydrase Inhibitors

Topics

• Analgesics (therapeutic use)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, therapeutic use)
• Arthritis, Rheumatoid (drug therapy)
• Carbonic Anhydrase Inhibitors (chemical synthesis, chemistry, therapeutic use)
• Drug Design
• Humans
• Rats