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

Sunil Kumar Singh; Saibaba Vobbalareddy; Srinivasa Rao Kalleda; Shaikh Abdul Rajjak; Seshagiri Rao Casturi; Srinivasa Raju Datla; Rao N V S Mamidi; Ramesh Mullangi; Ravikanth Bhamidipati; Rajagopalan Ramanujam; Venkateswarlu Akella; Koteswar Rao Yeleswarapu

doi:10.1039/B402787F

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

Org Biomol Chem. 2004 Sep 7;2(17):2442-50. doi: 10.1039/B402787F. Epub 2004 Aug 11.

Authors

Sunil Kumar Singh¹, Saibaba Vobbalareddy, Srinivasa Rao Kalleda, Shaikh Abdul Rajjak, Seshagiri Rao Casturi, Srinivasa Raju Datla, Rao N V S Mamidi, Ramesh Mullangi, Ravikanth Bhamidipati, Rajagopalan Ramanujam, Venkateswarlu Akella, Koteswar Rao Yeleswarapu

Affiliation

¹ Discovery Chemistry, Discovery Research-Dr. Reddy's Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, India. [email protected]

PMID: 15326524
DOI: 10.1039/B402787F

Abstract

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.

MeSH terms

Animals
Celecoxib
Cyclooxygenase 1
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors / chemical synthesis*
Cyclooxygenase Inhibitors / pharmacokinetics
Cyclooxygenase Inhibitors / pharmacology*
Drug Design
Drug Evaluation, Preclinical
Humans
Membrane Proteins
Models, Molecular
Molecular Structure
Prostaglandin-Endoperoxide Synthases / drug effects*
Pyrazoles / administration & dosage
Pyrazoles / chemical synthesis*
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology*
Rats
Rats, Wistar
Structure-Activity Relationship
Sulfonamides / administration & dosage
Sulfonamides / chemical synthesis*
Sulfonamides / pharmacokinetics
Sulfonamides / pharmacology*
Time Factors

Substances

2-hydroxymethyl-4-(5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl)-1-benzenesulfonamide
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Membrane Proteins
Pyrazoles
Sulfonamides
Cyclooxygenase 1
Cyclooxygenase 2
PTGS1 protein, human
PTGS2 protein, human
Prostaglandin-Endoperoxide Synthases
Ptgs1 protein, rat
Celecoxib