4-(4-Cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as Selective Cyclooxygenase-2 Inhibitors:  Enhancement of the Selectivity by Introduction of a Fluorine Atom and Identification of a Potent, Highly Selective, and Orally Active COX-2 Inhibitor JTE-522

Abstract

A series of 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamide derivatives were synthesized and evaluated for their abilities to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes. In this series, substituent effects at the ortho position to the sulfonamide group on the phenyl ring were examined. Most substituents reduced or lost both COX-2 and COX-1 activities. In contrast, introduction of a fluorine atom preserved COX-2 potency and notably increased COX1/COX-2 selectivity. This work led to the identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522 [9d, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide], which is currently in phase II clinical trials for the treatment of rheumatoid arthritis, osteoarthritis, and acute pain.

CoMFA/CoMSIA/HQSAR and Docking Study of the Binding Mode of Selective Cyclooxygenase (COX‐2) Inhibitors

“…The complexes formed by A9 of oxazoles, B2 of pyrazoles, C13 of pyrroles and D59 of imidazoles with COX-2 receptor were then investigated, as shown in Figure 2. For all complexes, two oxygen atoms of sulphonamide are linked by hydrogen bond to residues His90 and Arg513. This is consistent with the investigation reported by R. G. Kurumbail et al [6]. Beside these hydrogen bond interactions, there are also hydrophobic effects around sulphonamide group bonded to phenyl with the residues Phe518, Leu352, Leu359, Trp387 and Met522.…”

“…But extended use of NSAIDs, such as ibuprofen, may increase the risk of developing Alzheimer disease up to 80% [5]. Therefore we need to develop more specific and efficient COX-2 inhibitors with improved safety profile [6].…”

Synthesis, Nematicidal and Antifungal Properties of Hybrid Heterocyclics

“…20 The other derivatives display antidepressant, 21 antiarthritic 22 and cerebroprotecting 23 properties. Some aryl pyrazoles were reported to be non-nucleoside human immunodeficiency virus (HIV-1) reverse transcriptase inhibitor, 24 COX-2 inhibitor, [25][26][27] activator of the nitric oxide receptor and to have soluble guanylate cyclase activity. 28 Nematodes are tiny worms, some of them are plant parasites, and can play an important role in the predisposition of the host plant to the invansion by secondary pathogens.…”

Simple and Efficient One-Pot Synthesis, Spectroscopic Characterization and Crystal Structure of Methyl 5-(4-Chlorobenzoyloxy)-1-phenyl-1H-pyrazole-3-carboxylate

“…These are important bio-active drug targets in the pharmaceutical industry, as they are the core structure of numerous biologically active compounds [4]. They possess a broad spectrum of approved biological activities, which includes anti-inflammatory [5], antipyretic [6], gastric secretion stimulatory [7], antidepressant [8], antibacterial [9], antifilarial agents [10], anti-obesity [11], estrogen receptor agonist [12], HIV-1 reverse transcriptase inhibitors [13] and anti-hyperglycemic activities [14]. In addition, many pyrazole derivatives are also used as insecticides, herbicides and fungicides [15].…”