RESUMEN
The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.
Asunto(s)
Antagonistas del Receptor de Adenosina A1/síntesis química , Antagonistas del Receptor de Adenosina A2/síntesis química , Indenos/síntesis química , Trastornos Parkinsonianos/tratamiento farmacológico , Pirimidinas/síntesis química , Receptor de Adenosina A2A/metabolismo , Antagonistas del Receptor de Adenosina A1/farmacocinética , Antagonistas del Receptor de Adenosina A1/farmacología , Antagonistas del Receptor de Adenosina A2/farmacocinética , Antagonistas del Receptor de Adenosina A2/farmacología , Administración Oral , Animales , Diseño de Fármacos , Femenino , Indenos/farmacocinética , Indenos/farmacología , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos BALB C , Trastornos Parkinsonianos/inducido químicamente , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.
Asunto(s)
Antagonistas del Receptor de Adenosina A1/síntesis química , Antagonistas del Receptor de Adenosina A2/síntesis química , Antiparkinsonianos/síntesis química , Indenos/síntesis química , Enfermedad de Parkinson/metabolismo , Pirimidinas/síntesis química , Receptor de Adenosina A2A/fisiología , Antagonistas del Receptor de Adenosina A1/farmacocinética , Antagonistas del Receptor de Adenosina A1/farmacología , Antagonistas del Receptor de Adenosina A2/farmacocinética , Antagonistas del Receptor de Adenosina A2/farmacología , Administración Oral , Animales , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacología , Callithrix , Modelos Animales de Enfermedad , Femenino , Indenos/farmacocinética , Indenos/farmacología , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos BALB C , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
A novel series of arylindenopyrimidines were identified as A(2A) and A(1) receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with methylene amine substituents. The compounds show excellent activity in mouse models of Parkinson's disease when dosed orally.
Asunto(s)
Antagonistas del Receptor de Adenosina A1 , Antagonistas del Receptor de Adenosina A2 , Aminas/química , Neurotransmisores/química , Pirimidinas/química , Aminas/síntesis química , Aminas/uso terapéutico , Animales , Catalepsia/tratamiento farmacológico , Modelos Animales de Enfermedad , Ratones , Neurotransmisores/síntesis química , Neurotransmisores/uso terapéutico , Pirimidinas/síntesis química , Pirimidinas/uso terapéutico , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A2A/metabolismo , Relación Estructura-ActividadRESUMEN
Two reactive metabolites were identified in vivo for the dual A(2A)/A(1) receptor antagonist 1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with 1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity.