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1.
J Chem Inf Model ; 57(6): 1474-1487, 2017 06 26.
Artículo en Inglés | MEDLINE | ID: mdl-28463561

RESUMEN

Among non-dopaminergic strategies for combating Parkinson's disease (PD), antagonism of the A2A adenosine receptor (AR) has emerged to show great potential. In this study, on the basis of two crystal structures of the A2A AR with the best capability to distinguish known antagonists from decoys, docking-based virtual screening (VS) was conducted to identify novel A2A AR antagonists. A total of 63 structurally diverse compounds identified by VS were submitted to experimental testing, and 11 of them exhibited substantial activity against the A2A AR (Ki < 10 µM), including two compounds with Ki below 1 µM (compound 43, 0.42 µM; compound 51, 0.27 µM) and good A2A/A1 selectivity (fold < 0.1). Compounds 43 and 51 demonstrated antagonistic activity according to the results of cAMP measurements (cAMP IC50 = 1.67 and 1.80 µM, respectively) and showed good efficacy in the haloperidol-induced catalepsy (HIC) rat model for PD at doses of up to 30 mg/kg. Further lead optimization based on a substructure searching strategy led to the discovery of compound 84 as an excellent A2A AR antagonist (A2A Ki = 54 nM, A2A/A1 fold < 0.1, cAMP IC50 = 0.3 µM) that exhibited significant improvement in anti-PD efficacy in the HIC rat model.


Asunto(s)
Antagonistas del Receptor de Adenosina A2/química , Antagonistas del Receptor de Adenosina A2/farmacología , Evaluación Preclínica de Medicamentos/métodos , Enfermedad de Parkinson/tratamiento farmacológico , Receptor de Adenosina A2A/metabolismo , Antagonistas del Receptor de Adenosina A2/uso terapéutico , Animales , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Haloperidol/farmacología , Masculino , Modelos Moleculares , Conformación Molecular , Ratas , Ratas Wistar , Interfaz Usuario-Computador
2.
ACS Chem Neurosci ; 7(11): 1575-1584, 2016 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-27569066

RESUMEN

Adenosine receptor A2A antagonists have emerged as potential treatment for Parkinson's disease in the past decade. We have recently reported a series of adenosine receptor antagonists using heterocycles as bioisosteres for a potentially unstable acetamide. These compounds, while showing excellent potency and ligand efficiency, suffered from moderate cytochrome P450 inhibition and high clearance. Here we report a new series of adenosine receptor A2A antagonists based on a 4-amino-5-carbonitrile pyrimidine template. Compounds from this new template exhibit excellent potency and ligand efficiency with low cytochrome P450 inhibition. Although the clearance remains moderate to high, the leading compound, when dosed orally as low as 3 mg/kg, demonstrated excellent efficacy in the haloperidol induced catalepsy rat model for Parkinson's disease.


Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Antiparkinsonianos/farmacología , Pirimidinas/farmacología , Antagonistas del Receptor de Adenosina A2/síntesis química , Antagonistas del Receptor de Adenosina A2/farmacocinética , Animales , Antiparkinsonianos/síntesis química , Antiparkinsonianos/farmacocinética , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Haloperidol , Humanos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Simulación del Acoplamiento Molecular , Estructura Molecular , Trastornos Parkinsonianos/tratamiento farmacológico , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Relación Estructura-Actividad
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