Synthesis and cyclooxygenase-2 inhibiting property of 1,5-diarylpyrazoles with substituted benzenesulfonamide moiety as pharmacophore: Preparation of sodium salt for injectable formulation

Manojit Pal; Manjula Madan; Srinivas Padakanti; Vijaya R Pattabiraman; Srinivas Kalleda; Akhila Vanguri; Ramesh Mullangi; N V S Rao Mamidi; Seshagiri R Casturi; Alpeshkumar Malde; B Gopalakrishnan; Koteswar R Yeleswarapu

doi:10.1021/jm020563g

Synthesis and cyclooxygenase-2 inhibiting property of 1,5-diarylpyrazoles with substituted benzenesulfonamide moiety as pharmacophore: Preparation of sodium salt for injectable formulation

J Med Chem. 2003 Sep 11;46(19):3975-84. doi: 10.1021/jm020563g.

Authors

Manojit Pal¹, Manjula Madan, Srinivas Padakanti, Vijaya R Pattabiraman, Srinivas Kalleda, Akhila Vanguri, Ramesh Mullangi, N V S Rao Mamidi, Seshagiri R Casturi, Alpeshkumar Malde, B Gopalakrishnan, Koteswar R Yeleswarapu

Affiliation

¹ Discovery-Chemistry, Dr Reddy's Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500050, India. manojitpal@drreddys.com

PMID: 12954051
DOI: 10.1021/jm020563g

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.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Benzenesulfonamides
Binding Sites
Cyclooxygenase 1
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors / chemical synthesis*
Cyclooxygenase Inhibitors / chemistry
Cyclooxygenase Inhibitors / pharmacokinetics
Cyclooxygenase Inhibitors / pharmacology*
Edema / chemically induced
Edema / drug therapy
Humans
Inhibitory Concentration 50
Isoenzymes / antagonists & inhibitors*
Male
Membrane Proteins
Models, Molecular
Prostaglandin-Endoperoxide Synthases
Pyrazoles / chemical synthesis*
Pyrazoles / chemistry
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology*
Rats
Rats, Wistar
Sheep
Sodium / chemistry*
Spodoptera
Structure-Activity Relationship
Sulfonamides / chemistry*
Sulfonamides / pharmacokinetics
Sulfonamides / pharmacology*

Substances

Anti-Inflammatory Agents, Non-Steroidal
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Isoenzymes
Membrane Proteins
Pyrazoles
Sulfonamides
Sodium
Cyclooxygenase 1
Cyclooxygenase 2
PTGS1 protein, human
PTGS2 protein, human
Prostaglandin-Endoperoxide Synthases
Ptgs1 protein, rat