RESUMO
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.
Assuntos
Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Aminas/química , Neurotransmissores/química , Pirimidinas/química , Aminas/síntese química , Aminas/uso terapêutico , Animais , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Neurotransmissores/síntese química , Neurotransmissores/uso terapêutico , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Neurotransmissores/química , Pirimidinas/química , Animais , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Neurotransmissores/síntese química , Neurotransmissores/uso terapêutico , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
The p38 MAP kinase is thought to be involved in a variety of inflammatory and immunological disorders such as rheumatoid arthritis. The pyridinylimidazole class of compounds was the first to potently inhibit this kinase. Since the original reports of their efficacy, they have become the most widely studied series of inhibitors of this kinase. This framework has served as a starting point for further synthetic work and several compounds have entered clinical trials. These compounds have also been utilized to elucidate the role of p38 kinase in the immune system, and more recently have been used to examine the role of this kinase in central nervous system disorders.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Animais , Antirreumáticos/química , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Desenho de Fármacos , Humanos , Indóis/química , Indóis/farmacologia , Proteínas Quinases Ativadas por Mitógeno/imunologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Oxazóis/química , Oxazóis/farmacologia , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
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
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.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Ésteres/química , Camundongos , Estrutura Molecular , Piperazina , Piperazinas/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Methylisocyanoacetate undergoes a 2 + 3 cycloaddition with alpha,beta-unsaturated nitriles to provide a regioselective synthesis of 2-substituted 3,4-diaryl pyrroles. The ease of preparation of alpha,beta-unsaturated nitriles allows the rapid synthesis of pyrroles with varied substituents. Using this method, a key intermediate (1) for the synthesis of the marine natural products lukianol A, lamellarin O, and lamellarin Q was prepared in two steps. A total synthesis of ningalin B (11) was also accomplished utilizing this methodology.