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
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.
Asunto(s)
Antagonistas del Receptor de Adenosina A1 , Antagonistas del Receptor de Adenosina A2 , Neurotransmisores/química , Pirimidinas/química , 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
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
As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
Asunto(s)
Benzopiranos/química , Benzopiranos/farmacología , Posmenopausia/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Benzopiranos/síntesis química , Benzopiranos/uso terapéutico , Resorción Ósea/tratamiento farmacológico , Línea Celular Tumoral , Colesterol/sangre , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Femenino , Sofocos/tratamiento farmacológico , Humanos , Tamaño de los Órganos/efectos de los fármacos , Ovariectomía , Posmenopausia/sangre , Ratas , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Relación Estructura-Actividad , Especificidad por Sustrato , Útero/patología , Vagina/efectos de los fármacos , Vagina/metabolismoRESUMEN
Through an in vivo screening model, we developed the in vivo SAR of beta-alkylthio indolyl carbinols. Through these efforts we identified a compound with potent oral in vivo efficacy in both immature and mature rat prostate weight reduction models and in a murine xenograft prostate cancer model.
Asunto(s)
Antagonistas de Andrógenos/síntesis química , Antagonistas de Andrógenos/farmacología , Antineoplásicos/síntesis química , Química Farmacéutica/métodos , Indoles/síntesis química , Metanol/análogos & derivados , Metanol/química , Neoplasias de la Próstata/tratamiento farmacológico , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Modelos Animales de Enfermedad , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Indoles/farmacología , Masculino , Ratones , Trasplante de Neoplasias , Ratas , Relación Estructura-ActividadRESUMEN
Inhibition of the p38 map kinase pathway has been shown to be beneficial in the treatment of inflammatory diseases. The first class of potent p38 kinase inhibitors was the pyridinylimidazole compounds from SKB. Since then several pyridinylimidazole-based compounds have been shown to inhibit activated p38 kinase in vitro and in vivo. We have developed a novel series of pyridinylimidazole-based compounds, which potently inhibit the p38 pathway by binding to unactivated p38 kinase and only weakly inhibiting activated p38 kinase activity in vitro.