title: Synthesis and SAR/3D-QSAR studies on the COX-2 inhibitory activity of 1,5-diarylpyrazoles to validate the modified pharmacophore.
abstract: Diverse analogs of 1,5-diarylpyrazoles having 3-hydroxymethyl-4-sulfamoyl (SO2NH2)/methyl sulfonyl (SO2Me)-pheny group at N1 were synthesized and evaluated for their in vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The SAR study mainly involved the variations at positions C-3, C-5 and N1 of the pyrazole ring. Several small hydrophobic groups at/around position-4 of C-5 phenyl, viz. 3,4-dimethylphenyl analog 9, 3-methyl-4-methylsulfanylphenyl analog 14 and 2,3-dihydrobenzo[b]thiophenyl analog 17, exhibited impressive COX-2 inhibitory potency. In general, the sulfonamide analogues with a CHF2 at C-3 were found to be more potent than those having a CF3 group. The three dimensional quantitative structure activity relationship comprising comparative molecular field analysis (3D-QSAR-CoMFA) afforded the models with high predictivity which further validated the acceptance of hydroxymethyl (CH2OH) group in the hydrophilic pocket of the COX-2 enzyme.
authors.affiliation: Discovery Chemistry, Discovery Research-Dr. Reddy's Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, India. sunilkumarsingh@drreddys.com
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Singh
authors.forename: V
authors.initials: V
authors.lastname: Saibaba
authors.forename: K Srinivasa
authors.initials: KS
authors.lastname: Rao
authors.forename: P Ganapati
authors.initials: PG
authors.lastname: Reddy
authors.forename: Pankaj R
authors.initials: PR
authors.lastname: Daga
authors.forename: S Abdul
authors.initials: SA
authors.lastname: Rajjak
authors.forename: Parimal
authors.initials: P
authors.lastname: Misra
authors.forename: Y Koteswar
authors.initials: YK
authors.lastname: Rao
mesh_terms: D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
chemical_list: D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D051546:Cyclooxygenase 2