RESUMO
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.
Assuntos
Benzotiazóis/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Febre/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Pró-Fármacos/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Oral , Animais , Benzotiazóis/química , Benzotiazóis/farmacocinética , Carragenina/toxicidade , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Edema/induzido quimicamente , Edema/tratamento farmacológico , Endotoxinas/toxicidade , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Febre/induzido quimicamente , Pé , Humanos , Hiperalgesia/induzido quimicamente , Injeções Espinhais , Masculino , Microssomos/enzimologia , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Ratos , Ratos Wistar , Glândulas Seminais/enzimologia , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologiaRESUMO
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.
Assuntos
Ciclo-Oxigenase 2/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Pró-Fármacos/farmacologia , Sulfonamidas/farmacologia , Acilação , Animais , Área Sob a Curva , Disponibilidade Biológica , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacocinética , Pró-Fármacos/química , Ratos , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMO
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.
Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Indometacina/análogos & derivados , Animais , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/toxicidade , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Avaliação Pré-Clínica de Medicamentos , Edema/tratamento farmacológico , Humanos , Ligação de Hidrogênio , Técnicas In Vitro , Indometacina/química , Indometacina/farmacologia , Indometacina/toxicidade , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Wistar , Glândulas Seminais/efeitos dos fármacos , Glândulas Seminais/enzimologia , Ovinos , Úlcera Gástrica/induzido quimicamenteRESUMO
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.
Assuntos
Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/farmacologia , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Pirazóis/síntese química , Pirazóis/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Celecoxib , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacocinética , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Proteínas de Membrana , Modelos Moleculares , Estrutura Molecular , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Fatores de TempoRESUMO
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.
Assuntos
Inibidores de Ciclo-Oxigenase/química , Isoenzimas/antagonistas & inibidores , Pirazóis/química , Sulfonamidas/química , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Humanos , Isoenzimas/metabolismo , Proteínas de Membrana , Prostaglandina-Endoperóxido Sintases/metabolismo , Pirazóis/farmacologia , Sulfonamidas/farmacologiaRESUMO
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.