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.
J Med Chem. 2017 Feb 9;60(3):1159-1170. doi: 10.1021/acs.jmedchem.6b01607. Epub 2017 Jan 23.
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 K 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.
我们报告了一系列杂合化合物的合成，这些化合物包含 6-和 7-取代香豆素（碳酸酐酶，CA 抑制剂），并用临床使用的非甾体抗炎药（吲哚美辛、舒林酸、酮洛芬、布洛芬、双氯芬酸、酮咯酸等，环氧化酶抑制剂）衍生化，作为治疗类风湿关节炎（RA）的药物。大多数化合物能有效抑制过表达的 RA hCAIX 和 XII，其 K 值在低纳摩尔-亚纳摩尔范围内。通过使用体内 RA 模型的爪压和失能试验来评估这些化合物的抗痛觉过敏活性。在所测试的所有化合物中，与布洛芬的 7-香豆素杂合化合物在给药后 60 分钟内显示出强大且持久的抗痛觉过敏作用。
