Identification of 2-hydroxymethyl-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-pyrazol-1-yl]-N-propionylbenzenesulfonamide sodium as a potential COX-2 inhibitor for oral and parenteral administration.
Synthesis of prodrugs of orally active COX-2 inhibitor 3 involving sulfamoyl (SO(2)NH(2)) and hydroxymethyl (CH(2)OH) groups, and their biological evaluation are described. Of these prodrugs, the N-propionyl sulfonamide sodium 3k was found to be much superior to the parent compound 3 and other marketed COX-2 inhibitors in carrageenan induced rat paw edema model of inflammation due to highly elevated drug levels in systemic circulation. This prodrug has a potential both for oral as well as parenteral administration due to impressive analgesic activity, antipyretic potency, and extraordinary water solubility.
Singh
Sunil Kumar
SK
Discovery Chemistry, Discovery Research-Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India. sunilkumarsingh@drreddys.com
Vobbalareddy
Saibaba
S
Kalleda
Srinivasa Rao
SR
Casturi
Seshagiri Rao
SR
Datla
Srinivasa Raju
SR
Mamidi
Rao N V S
RN
Mullangi
Ramesh
R
Ramanujam
Rajagopalan
R
Yeleswarapu
Koteswar Rao
KR
Iqbal
Javed
J
D000284:Administration, Oral; D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D002351:Carrageenan / Q000633:toxicity; D051545:Cyclooxygenase 1 / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000737:chemistry; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004731:Endotoxins / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy*; D005528:Foot; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D007278:Injections, Spinal; D008297:Male; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012669:Seminal Vesicles / Q000201:enzymology; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D000096926:Benzenesulfonamides
D052160:Benzothiazoles; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D004731:Endotoxins; D004791:Enzyme Inhibitors; D011355:Prodrugs; D013449:Sulfonamides; C516703:2-hydroxymethyl-4-(5-(4-methoxyphenyl)-3-trifluoromethylpyrazol-1-yl)-N-propionylbenzenesulfonamide; D000096926:Benzenesulfonamides