ABSTRACT
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.
Subject(s)
Benzothiazoles/administration & dosage , Cyclooxygenase 2 Inhibitors/administration & dosage , Enzyme Inhibitors/administration & dosage , Fever/drug therapy , Hyperalgesia/drug therapy , Prodrugs/administration & dosage , Sulfonamides/administration & dosage , Administration, Oral , Animals , Benzothiazoles/chemistry , Benzothiazoles/pharmacokinetics , Carrageenan/toxicity , Cyclooxygenase 1/chemistry , Cyclooxygenase 2/chemistry , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/pharmacology , Edema/chemically induced , Edema/drug therapy , Endotoxins/toxicity , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Fever/chemically induced , Foot , Humans , Hyperalgesia/chemically induced , Injections, Spinal , Male , Microsomes/enzymology , Molecular Structure , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Rats , Rats, Wistar , Seminal Vesicles/enzymology , Solubility , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
Synthesis and biological evaluation of possible prodrugs of COX-2 inhibitors involving sulfonamide and hydroxymethyl groups of 2-hydroxymethyl-4-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl) benzenesulfonamides are described. Out of many options, the sodium salt of N-propionyl sulfonamide demonstrated much improved pharmacological profiles and physicochemical properties suitable for oral as well as parenteral administration.
Subject(s)
Cyclooxygenase 2/drug effects , Cyclooxygenase Inhibitors/pharmacology , Prodrugs/pharmacology , Sulfonamides/pharmacology , Acylation , Animals , Area Under Curve , Biological Availability , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/pharmacokinetics , Prodrugs/chemistry , Rats , Sulfonamides/chemistry , Sulfonamides/pharmacokineticsABSTRACT
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.
