title: 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.
authors.affiliation: Discovery-Chemistry, Dr Reddy's Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500050, India. manojitpal@drreddys.com
authors.forename: Manojit
authors.initials: M
authors.lastname: Pal
authors.forename: Manjula
authors.initials: M
authors.lastname: Madan
authors.forename: Srinivas
authors.initials: S
authors.lastname: Padakanti
authors.forename: Vijaya R
authors.initials: VR
authors.lastname: Pattabiraman
authors.forename: Srinivas
authors.initials: S
authors.lastname: Kalleda
authors.forename: Akhila
authors.initials: A
authors.lastname: Vanguri
authors.forename: Ramesh
authors.initials: R
authors.lastname: Mullangi
authors.forename: N V S Rao
authors.initials: NV
authors.lastname: Mamidi
authors.forename: Seshagiri R
authors.initials: SR
authors.lastname: Casturi
authors.forename: Alpeshkumar
authors.initials: A
authors.lastname: Malde
authors.forename: B
authors.initials: B
authors.lastname: Gopalakrishnan
authors.forename: Koteswar R
authors.initials: KR
authors.lastname: Yeleswarapu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008565:Membrane Proteins; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012756:Sheep; D012964:Sodium / Q000737:chemistry*; D018411:Spodoptera; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D012964:Sodium; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C496513:Ptgs1 protein, rat