ChemMedChem

Cover image for Vol. 10 Issue 5

Editor-in-Chief: Natalia Ortúzar

Impact Factor: 3.046

ISI Journal Citation Reports © Ranking: 2013: 18/58 (Chemistry Medicinal); 75/256 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

October 11, 2011

VIP: Rofecoxib Analogues Possessing a Nitric Oxide Donor Sulfohydroxamic Acid (SO2NHOH) Cyclooxygenase-2 Pharmacophore: Synthesis, Molecular Modeling, and Biological Evaluation as Anti-inflammatory Agents

VIP: Rofecoxib Analogues Possessing a Nitric Oxide Donor Sulfohydroxamic Acid (SO2NHOH) Cyclooxygenase-2 Pharmacophore: Synthesis, Molecular Modeling, and Biological Evaluation as Anti-inflammatory AgentsAtul Bhardwaj, Zhangjian Huang, Jatinder Kaur, Edward E. Knaus*

The discoveries of celecoxib, rofecoxib, and valdecoxib represent important milestones in validating the original drug design concept that selective cyclooxygenase-2 (COX-2) inhibitors would show a low risk of gastrointestinal irritation, bleeding, and ulcerogenicity. Unfortunately, chronic use of highly selective COX-2 inhibitors such as rofecoxib causes a biochemical imbalance wherein the level of the beneficial vasodilatory and anti-platelet-aggregatory prostacyclin is decreased in conjunction with a simultaneous undesirable increase in the level of thromboxane A2, which induces vasoconstriction and promotes platelet aggregation.

Edward Knaus and his postdoctoral fellows at the University of Alberta (Canada) discovered that replacement of the SO2Me substituent in rofecoxib by a nitric oxide (NO) donor sulfohydroxamic acid (SO2NHOH) COX-2 pharmacophore is a viable approach for circumventing the adverse elevation of blood pressure and increased prevalence of blood clots and stroke cases which prompted the withdrawal of rofecoxib. This approach was based on the fact that NO is a vasorelaxant and inhibitor of platelet aggregation. Based on the concept of obstructive metabolic halogenation and results of molecular modeling experiments, Knaus and co-workers synthesized a group of stable and readily isolated candidate lead compounds. Biological studies identified N-hydroxy-4-[4-(4-chlorophenyl)-5-oxo-2,5-dihydrofuran-3-yl]benzenesulfonamide as a superior compound that: 1) is a potent and selective inhibitor of the COX-2 isozyme, 2) is an effective NO donor at physiological pH, and 3) exhibits significant anti-inflammatory activity.

Molecular modeling studies showed that the SO2NHOH moiety is an effective COX-2 pharmacophore that undergoes multiple hydrogen bonding interactions to the binding site of COX-2, but not that of COX-1. The results show that the incorporation of an NO donor SO2NHOH COX-2 pharmacophore offers a rational drug design approach to circumvent adverse thrombotic and hypertensive effects associated with the chronic use of selective COX-2 inhibitors.

Received August 15, 2011; published online October 11, 2011, DOI: 10.1002/cmdc.201100393.

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