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J Med Chem. 2017 Feb 9;60(3):1159-1170. doi: 10.1021/acs.jmedchem.6b01607. Epub 2017 Jan 23.

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

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NEUROFARBA, Sezione di Scienze Farmaceutiche, University of Florence , Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
Department of Neuroscience, Psychology, Drug Research and Child Health, NEUROFARBA-Pharmacology and Toxicology Section, University of Florence , 50019 Florence, Italy.
Polo Scientifico, Laboratorio di Chimica Bioinorganica, University of Florence , Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.


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.

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