RESUMO
Recently, we disclosed a series of potent pyrimidine benzamide-based thrombopoietin receptor agonists. Unfortunately, the structural features required for the desired activity conferred physicochemical properties that were not favorable for the development of an oral agent. The physical properties of the series were improved by replacing the aminopyrimidinyl group with a piperidine-4-carboxylic acid moiety. The resulting compounds possessed favorable in vivo pharmacokinetic properties, including good bioavailability.
Assuntos
Benzoatos/química , Benzoatos/metabolismo , Hidrazinas/química , Hidrazinas/metabolismo , Pirazóis/química , Pirazóis/metabolismo , Receptores de Trombopoetina/agonistas , Receptores de Trombopoetina/metabolismo , Administração Oral , Animais , Benzoatos/administração & dosagem , Disponibilidade Biológica , Células CACO-2 , Humanos , Hidrazinas/administração & dosagem , Piperidinas/síntese química , Piperidinas/metabolismo , Pirazinamida/análogos & derivados , Pirazinamida/síntese química , Pirazinamida/metabolismo , Pirazóis/administração & dosagem , Pirimidinas/síntese química , Pirimidinas/metabolismo , RatosRESUMO
A series of pyrimidine benzamide-based thrombopoietin receptor agonists is described. The lead molecule contains a 2-amino-5-unsubstituted thiazole, a group that has been associated with idiosyncratic toxicity. The potential for metabolic oxidation at C-5 of the thiazole, the likely source of toxic metabolites, was removed by substitution at C-5 or by replacing the thiazole with a thiadiazole. Potency in the series was improved by modifying the substituents on the pyrimidine and/or on the thiazole or thiadiazole pendant aryl ring. In vivo examination revealed that compounds from the series are not highly bioavailable. This is attributed to low solubility and poor permeability.