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
A number of novel indomethacin glycolamide esters were synthesized and tested for their cyclooxygenase (COX-1 and COX-2) inhibition properties in vitro. Many of these compounds proved to be selective COX-2 inhibitors, and subtle structural changes in the substituents on the glycolamide ester moiety altered the inhibitory properties as well as potencies significantly. Their in vitro data were rationalized through molecular modeling studies. Few of them displayed anti-inflammatory activity in vivo. Compound 32, [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid 2-morpholin-4-yl-2-oxo ethyl ester, was identified as a promising compound in this class and its good anti-inflammatory activity was demonstrated in the in vivo model.
Subject(s)
Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Indomethacin/analogs & derivatives , Animals , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/toxicity , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/pharmacology , Drug Evaluation, Preclinical , Edema/drug therapy , Humans , Hydrogen Bonding , In Vitro Techniques , Indomethacin/chemistry , Indomethacin/pharmacology , Indomethacin/toxicity , Male , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Models, Molecular , Molecular Structure , Rats , Rats, Wistar , Seminal Vesicles/drug effects , Seminal Vesicles/enzymology , Sheep , Stomach Ulcer/chemically inducedABSTRACT
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.
Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Prostaglandin-Endoperoxide Synthases/drug effects , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Animals , Celecoxib , Cyclooxygenase 1 , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacokinetics , Drug Design , Drug Evaluation, Preclinical , Humans , Membrane Proteins , Models, Molecular , Molecular Structure , Pyrazoles/administration & dosage , Pyrazoles/pharmacokinetics , Rats , Rats, Wistar , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Time FactorsABSTRACT
The effect of methanesulfonamide (MeSO(2)NH) group on COX-2 inhibitory activity of 1,5-diarylpyrazole is described. While this group being at position-4 of the N(1)-phenyl ring was found to be ineffective, its installation at position-4 of the C-5 phenyl ring offered several potent and selective inhibitors of COX-2 with IC(50) as low as 30 nM.
Subject(s)
Cyclooxygenase Inhibitors/chemistry , Isoenzymes/antagonists & inhibitors , Pyrazoles/chemistry , Sulfonamides/chemistry , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Humans , Isoenzymes/metabolism , Membrane Proteins , Prostaglandin-Endoperoxide Synthases/metabolism , Pyrazoles/pharmacology , Sulfonamides/pharmacologyABSTRACT
New 3-O-substituted benzyl pyridazinone compounds have been synthesised and evaluated for their cyclooxygenase inhibitory activity and COX-2 selectivity. Among the compounds synthesised, three compounds (11b-11d) have shown in vitro COX-2 selectivity. These compounds have been evaluated for their in vivo potential using carrageenan-induced rat paw edema assay. One compound (11b) showed 32% anti-inflammatory activity at 30 mgkg(-1) dose.
