2-hydroxymethyl-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide (DRF-4367): an orally active COX-2 inhibitor identified through pharmacophoric modulation.
Analogs of 1,5-diarylpyrazoles with a novel pharmacophore at N1 were designed, synthesized and evaluated for the in-vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The variations at/around position-4 of the C-5 phenyl ring in conjunction with a CF3 and CHF2 groups at C-3 exhibited a high degree of potency and selectivity index (SI) for COX-2 inhibition. The in-vivo evaluation of these potent compounds with a few earlier ones indicated the 4-OMe-phenyl analog and the 4-NHMe-phenyl analog with a CF3, and the 4-OEt-phenyl analog with a CHF2 group at C-3 to possess superior potency than celecoxib. In addition to its impressive anti-inflammatory, antipyretic, analgesic and anti-arthritic properties, compound (DRF-4367) was found to possess an excellent pharmacokinetic profile, gastrointestinal (GI) safety in the long-term arthritis study and COX-2 potency in human whole blood assay. Thus, compound was selected as an orally active anti-inflammatory candidate for pre-clinical evaluation.
Discovery Chemistry, Discovery Research-Dr. Reddy's Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, India. sunilkumarsingh@drreddys.com
Sunil Kumar
SK
Singh
Saibaba
S
Vobbalareddy
Srinivasa Rao
SR
Kalleda
Shaikh Abdul
SA
Rajjak
Seshagiri Rao
SR
Casturi
Srinivasa Raju
SR
Datla
Rao N V S
RN
Mamidi
Ramesh
R
Mullangi
Ravikanth
R
Bhamidipati
Rajagopalan
R
Ramanujam
Venkateswarlu
V
Akella
Koteswar Rao
KR
Yeleswarapu
D000818:Animals; D000068579:Celecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008565:Membrane Proteins; D008958:Models, Molecular; D015394:Molecular Structure; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D011720:Pyrazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors; D000096926:Benzenesulfonamides
D000068579:Celecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D013449:Sulfonamides; C482791:2-hydroxymethyl-4-(5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl)-1-benzenesulfonamide; D000096926:Benzenesulfonamides; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C496513:Ptgs1 protein, rat