RESUMO
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.
Assuntos
Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/síntese química , Indenos/síntese química , Transtornos Parkinsonianos/tratamento farmacológico , Pirimidinas/síntese química , Receptor A2A de Adenosina/metabolismo , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Antagonistas do Receptor A1 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Antagonistas do Receptor A2 de Adenosina/farmacologia , Administração Oral , Animais , Desenho de Fármacos , Feminino , Indenos/farmacocinética , Indenos/farmacologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transtornos Parkinsonianos/induzido quimicamente , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/síntese química , Antiparkinsonianos/síntese química , Indenos/síntese química , Doença de Parkinson/metabolismo , Pirimidinas/síntese química , Receptor A2A de Adenosina/fisiologia , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Antagonistas do Receptor A1 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Antagonistas do Receptor A2 de Adenosina/farmacologia , Administração Oral , Animais , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Callithrix , Modelos Animais de Doenças , Feminino , Indenos/farmacocinética , Indenos/farmacologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
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.
Assuntos
Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/farmacologia , Antineoplásicos/síntese química , Química Farmacêutica/métodos , Indóis/síntese química , Metanol/análogos & derivados , Metanol/química , Neoplasias da Próstata/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Modelos Animais de Doenças , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Indóis/farmacologia , Masculino , Camundongos , Transplante de Neoplasias , Ratos , Relação Estrutura-AtividadeRESUMO
A practical preparation of an alpha(v)beta(3) antagonist is reported. The antagonist consists of three key components, a tetrahydronaphthyridine moiety, a beta-alanine moiety, and a central imidazolidone moiety. The tetrahydronaphthyridine component was prepared using two different methods, both of which relied on variations of the Friedländer reaction to establish the desired regiochemistry. The beta-alanine component was prepared using Davies' asymmetric 1,4-addition methodology as the key stereo-defining step. The central imidazolidone portion was created from these two components using an effective three-step cyclization protocol. Thus, a highly convergent process for the drug candidate was defined.