Synthesis and Cyclooxygenase-2 Inhibiting Property of 1,5-Diarylpyrazoles with Substituted Benzenesulfonamide Moiety as Pharmacophore:  Preparation of Sodium Salt for Injectable Formulation^†

Abstract

A series of 1,5-diarylpyrazoles having a substituted benzenesulfonamide moiety as pharmacophore was synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities. Through SAR and molecular modeling, it was found that fluorine substitution on the benzenesulfonamide moiety along with an electron-donating group at the 4-position of the 5-aryl ring yielded selectivity as well as potency for COX-2 inhibition in vitro. Among such compounds 3-fluoro-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide 3 displayed interesting pharmacokinetic properties along with antiinflammatory activity in vivo. Among the sodium salts tested in vivo, 10, the propionyl analogue of 3, showed excellent antiinflammatory activity and therefore represents a new lead structure for the development of injectable COX-2 specific inhibitors.

Biotransformation of Celecoxib Using Microbial Cultures

“…The pathway for the formation of this metabolite from celecoxib might involve direct acetylation of amino group. This metabolite was reported to be 3.3 times more potent inhibitor toward COX-1 than COX-2 [42].…”

Current Status of COX-2 Inhibitors

“…onto the most vital 4-sulfamoyl (SO 2 NH 2 )-phenyl ring of celecoxib provided compounds 40, 41 and 42 (Chart 13). Compound 40 shows 75% and 13% inhibitions of COX-2 and COX-1 respectively at 10 M concentrations [35] while celecoxib exhibits 100% and 0% inhibitions of COX-2 and COX-1 at same concentrations. Remarkably, in this contribution [35] a water soluble prodrug (41) with good in-vivo activity has been developed.…”

“…Compound 40 shows 75% and 13% inhibitions of COX-2 and COX-1 respectively at 10 M concentrations [35] while celecoxib exhibits 100% and 0% inhibitions of COX-2 and COX-1 at same concentrations. Remarkably, in this contribution [35] a water soluble prodrug (41) with good in-vivo activity has been developed. Compound 42 has been reported to be superior to celecoxib on the basis of its anti-inflammatory, antipyretic, analgesic and anti-arthritic potential [36][37][38][39].…”

A review of recent progress (2002-2012) on the biological activities of pyrazoles

“…220 Compound 221 had similar potency and selectivity to Celecoxib in enzyme assays. 221 In the course of this review several compounds bearing CF3 substituents have been mentioned: 1, 4, 49, 50, 52, 58, 62, 63, 66, 68, 70, 71, 72, 73 and 74. These structures belong to Sections 3 (Heterocycles) and 4 (Amides).…”