Malvina Hoxha1, Carola Buccellati1, Valérie Capra2, Davide Garella3, Clara Cena3, Barbara Rolando3, Roberta Fruttero3, Silvia Carnevali1, Angelo Sala1, G Enrico Rovati4, Massimo Bertinaria3. 1. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy. 2. Dipartimento di Scienze della Salute, Università degli Studi di Milano, via di Rudinì 8, 20142 Milano, Italy. 3. Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125 Torino, Ital. 4. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy. Electronic address: genrico.rovati@unimi.it.
Abstract
PURPOSE: Patients with high cardiovascular risk due to ageing and/or comorbidity (diabetes, atherosclerosis) that require effective management of chronic pain may take advantage from new non-steroidal anti-inflammatory drugs (NSAIDs) that at clinical dosages may integrate the anti-inflammatory activity and reduced gastrointestinal side effects of selective cyclooxygenase-2 (COX-2) inhibitor (coxib) with a cardioprotective component involving antagonism of thromboxane A2 prostanoid (TP) receptor. METHODS: New compounds were obtained modulating the structure of the most potent coxib, lumiracoxib, to obtain novel multitarget NSAIDs endowed with balanced coxib and TP receptor antagonist properties. Antagonist activity at TP receptor (pA2) was evaluated for all compounds in human platelets and in an heterologous expression system by measuring prevention of aggregation and Gq-dependent production of intracellular inositol phosphate induced by the stable thromboxane A2 (TXA2) agonist U46619. COX-1 and COX-2 inhibitory activities were assessed in human washed platelets and lympho-monocytes suspension, respectively. COX selectivity was determined from dose-response curves by calculating a ratio (COX-2/COX-1) of IC50 values. RESULTS: The tetrazole derivative 18 and the trifluoromethan sulfonamido-isoster 20 were the more active antagonists at TP receptor, preventing human platelet aggregation and intracellular signalling, with pA2 values statistically higher from that of lumiracoxib. Comparative data regarding COX-2/COX-1 selectivity showed that while compounds 18 and 7 were rather potent and selective COX-2 inhibitor, compound 20 was somehow less potent and selective for COX-2. CONCLUSION: These results indicate that compounds 18 and 20 are two novel combined TP receptor antagonists and COX-2 inhibitors characterized by a fairly balanced COX-2 inhibitor activity and TP receptor antagonism and that they may represent a first optimization of the original structure to improve their multitarget activity.
PURPOSE:Patients with high cardiovascular risk due to ageing and/or comorbidity (diabetes, atherosclerosis) that require effective management of chronic pain may take advantage from new non-steroidal anti-inflammatory drugs (NSAIDs) that at clinical dosages may integrate the anti-inflammatory activity and reduced gastrointestinal side effects of selective cyclooxygenase-2 (COX-2) inhibitor (coxib) with a cardioprotective component involving antagonism of thromboxane A2 prostanoid (TP) receptor. METHODS: New compounds were obtained modulating the structure of the most potent coxib, lumiracoxib, to obtain novel multitarget NSAIDs endowed with balanced coxib and TP receptor antagonist properties. Antagonist activity at TP receptor (pA2) was evaluated for all compounds in human platelets and in an heterologous expression system by measuring prevention of aggregation and Gq-dependent production of intracellular inositol phosphate induced by the stable thromboxane A2 (TXA2) agonist U46619. COX-1 and COX-2 inhibitory activities were assessed in human washed platelets and lympho-monocytes suspension, respectively. COX selectivity was determined from dose-response curves by calculating a ratio (COX-2/COX-1) of IC50 values. RESULTS: The tetrazole derivative 18 and the trifluoromethan sulfonamido-isoster 20 were the more active antagonists at TP receptor, preventing humanplatelet aggregation and intracellular signalling, with pA2 values statistically higher from that of lumiracoxib. Comparative data regarding COX-2/COX-1 selectivity showed that while compounds 18 and 7 were rather potent and selective COX-2 inhibitor, compound 20 was somehow less potent and selective for COX-2. CONCLUSION: These results indicate that compounds 18 and 20 are two novel combined TP receptor antagonists and COX-2 inhibitors characterized by a fairly balanced COX-2 inhibitor activity and TP receptor antagonism and that they may represent a first optimization of the original structure to improve their multitarget activity.
Authors: Jan S Kramer; Stefano Woltersdorf; Thomas Duflot; Kerstin Hiesinger; Felix F Lillich; Felix Knöll; Sandra K Wittmann; Franca-M Klingler; Steffen Brunst; Apirat Chaikuad; Christophe Morisseau; Bruce D Hammock; Carola Buccellati; Angelo Sala; G Enrico Rovati; Matthieu Leuillier; Sylvain Fraineau; Julie Rondeaux; Victor Hernandez-Olmos; Jan Heering; Daniel Merk; Denys Pogoryelov; Dieter Steinhilber; Stefan Knapp; Jeremy Bellien; Ewgenij Proschak Journal: J Med Chem Date: 2019-09-17 Impact factor: 7.446
Authors: Qiao Han; Wang Bing; Yin Di; Li Hua; Li Shi-He; Zheng Yu-Hua; Han Xiu-Guo; Wang Yu-Gang; Fan Qi-Ming; Yang Shih-Mo; Tang Ting-Ting Journal: Cell Death Dis Date: 2016-09-01 Impact factor: 8.469
Authors: Fatima Z Alshbool; Zubair A Karim; Enma V Paez Espinosa; Olivia A Lin; Fadi T Khasawneh Journal: J Am Heart Assoc Date: 2018-06-23 Impact factor: 5.501