Synthesis and cyclooxygenase-2 inhibiting property of 1,5-diarylpyrazoles with substituted benzenesulfonamide moiety as pharmacophore: Preparation of sodium salt for injectable formulation.
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.
Pal
Manojit
M
Discovery-Chemistry, Dr Reddy's Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500050, India. manojitpal@drreddys.com
Madan
Manjula
M
Padakanti
Srinivas
S
Pattabiraman
Vijaya R
VR
Kalleda
Srinivas
S
Vanguri
Akhila
A
Mullangi
Ramesh
R
Mamidi
N V S Rao
NV
Casturi
Seshagiri R
SR
Malde
Alpeshkumar
A
Gopalakrishnan
B
B
Yeleswarapu
Koteswar R
KR
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
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