RESUMEN
A lipophilicity constrained library of 5-carboxamido 1-benzyl-3-(3-dimethylaminopropyloxy)-1H-pyrazoles was prepared by solution-phase parallel synthesis with removal of acidic by-products using the strongly basic MP-carbonate resin. Compounds show both activation of soluble guanylate cyclase and inhibition of platelet aggregation. Compound 12 also shows 22% oral bioavailability in rats.
Asunto(s)
Activadores de Enzimas/síntesis química , Activadores de Enzimas/farmacología , Guanilato Ciclasa/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Administración Oral , Animales , Disponibilidad Biológica , Colágeno/farmacología , GMP Cíclico/análisis , Concentración 50 Inhibidora , Pirazoles/síntesis química , Pirazoles/farmacología , RatasRESUMEN
Database searching and compound screening identified 1-benzyl-3-(3-dimethylaminopropyloxy)indazole (benzydamine, 3) as a potent activator of the nitric oxide receptor, soluble guanylate cyclase. A comprehensive structure-activity relationship study surrounding 3 clearly showed that the indazole C-3 dimethylaminopropyloxy substituent was critical for enzyme activity. However replacement of the indazole ring of 3 by appropriately substituted pyrazoles maintained enzyme activity. Compounds were evaluated for inhibition of platelet aggregation and showed a general lipophilicity requirement. Aryl-substituted pyrazoles 32, 34, and 43 demonstrated potent activation of soluble guanylate cyclase and potent inhibition of platelet aggregation. Pharmacokinetic studies in rats showed that compound 32 exhibits modest oral bioavailability (12%). Furthermore 32 has an excellent selectivity profile notably showing no significant inhibition of phosphodiesterases or nitric oxide synthases.