RESUMO
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
Assuntos
Acetamidas/síntese química , Antagonistas dos Receptores de Hormônios Antidiuréticos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , Acetamidas/química , Acetamidas/farmacologia , Animais , Células CACO-2 , Humanos , Concentração Inibidora 50 , Masculino , Estrutura Molecular , Quinazolinonas/química , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.
Assuntos
Amidas/química , Anti-Hipertensivos/química , Cicloexanóis/química , Isoxazóis/química , Canais de Cátion TRPV/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Cicloexanóis/síntese química , Cicloexanóis/farmacocinética , Hipertermia Induzida , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) (V(3)) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Quinazolinas/síntese química , Quinazolinas/farmacologia , Animais , Humanos , Quinazolinas/química , Quinazolinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.