RESUMO
The synthesis, SAR and binding affinities of cannabinoid-1 receptor (CB1R) inverse agonists based on furo[2,3-b]pyridine scaffolds are described. Food intake, mechanism specific efficacy, pharmacokinetic, and metabolic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
Assuntos
Desenho de Fármacos , Furanos/síntese química , Piridinas/síntese química , Receptor CB1 de Canabinoide/agonistas , Animais , Benzopiranos , Cães , Furanos/química , Furanos/farmacologia , Haplorrinos , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Knockout , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Ratos , Receptor CB1 de Canabinoide/genética , Relação Estrutura-AtividadeRESUMO
MRL-1, a cannabinoid receptor-1 inverse agonist, was a member of a lead candidate series for the treatment of obesity. In rats, MRL-1 is eliminated mainly via metabolism, followed by excretion of the metabolites into bile. The major metabolite M1, a glutathione conjugate of MRL-1, was isolated and characterized by liquid chromatography/mass spectrometry and NMR spectroscopic methods. The data suggest that the t-butylsulfonyl group at C-2 of furopyridine was displaced by the glutathionyl group. In vitro experiments using rat and monkey liver microsomes in the presence of reduced glutathione (GSH) showed that the formation of M1 was independent of NADPH and molecular oxygen, suggesting that this reaction was not mediated by an oxidative reaction and a glutathione S-transferase (GST) was likely involved in catalyzing this reaction. Furthermore, a rat hepatic GST was capable of catalyzing the conversion of MRL-1 to M1 in the presence of GSH. When a close analog of MRL-1, a p-chlorobenzenesulfonyl furopyridine derivative (MRL-2), was incubated with rat liver microsomes in the presence of GSH, p-chlorobenzene sulfinic acid (M2) was also identified as a product in addition to the expected M1. Based on these data, a mechanism is proposed involving direct nucleophilic addition of GSH to sulfonylfuropyridine, resulting in an unstable adduct that spontaneously decomposes to form M1 and M2.
Assuntos
Biocatálise , Glutationa Transferase/metabolismo , Piridinas/farmacocinética , Compostos de Enxofre/farmacocinética , Animais , Bile/química , Biotransformação/fisiologia , Cromatografia Líquida , Citosol/metabolismo , Cães , Glutationa/metabolismo , Haplorrinos , Humanos , Fígado/enzimologia , Espectroscopia de Ressonância Magnética , Masculino , Microssomos Hepáticos/enzimologia , Estrutura Molecular , NADP/metabolismo , Piridinas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/antagonistas & inibidores , Especificidade da Espécie , Compostos de Enxofre/metabolismo , Espectrometria de Massas em TandemRESUMO
Optimization of the biological activity for 5,6-diarylpyridines as CB1 receptor inverse agonists is described. Food intake and pharmacokinetic evaluation of 3f and 15c indicate that these compounds are effective orally active modulators of CB1.
Assuntos
Química Farmacêutica/métodos , Piridinas/química , Piridinas/síntese química , Receptor CB1 de Canabinoide/agonistas , Animais , Comportamento Animal/efeitos dos fármacos , Desenho de Fármacos , Comportamento Alimentar/efeitos dos fármacos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Temperatura , Tolueno/químicaRESUMO
Structure-activity relationship studies for two series of 2-benzyloxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyridines having either a 3-cyano or 3-carboxamide moiety resulted in the preparation of the 2-(3,4-difluorobenzyloxy)-3-nitrile analog 10d and the 2-(3,4-difluorobenzyloxy)-3-(N-propylcarboxamide) analog 16c, (hCB1 IC(50)=1.3 and 1.7 nM, respectively) as potent and selective hCB1 inverse agonists. Their synthesis and biological activities are described herein.
