RESUMO
A novel series of CXCR4 antagonists were identified based on the substantial redesign of AMD070. These compounds possessed potent anti-HIV-1 activity and showed excellent pharmacokinetics in rat and dog.
Assuntos
Fármacos Anti-HIV/síntese química , Desenho de Fármacos , HIV-1/efeitos dos fármacos , Receptores CXCR4/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Aminoquinolinas , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Benzimidazóis , Butilaminas , Replicação do DNA/efeitos dos fármacos , Cães , HIV-1/fisiologia , Compostos Heterocíclicos com 1 Anel/química , Estrutura Molecular , RatosRESUMO
An early lead from the AMD070 program was optimized and a structure-activity relationship was developed for a novel series of heterocyclic containing compounds. Potent CXCR4 antagonists were identified based on anti-HIV-1 activity and Ca(2+) flux inhibition that displayed good pharmacokinetics in rat and dog.
Assuntos
Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Receptores CXCR4/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Administração Oral , Aminoquinolinas , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Benzimidazóis , Butilaminas , Sinalização do Cálcio , Cães , HIV-1/fisiologia , Compostos Heterocíclicos com 1 Anel/química , Humanos , Ratos , Receptores CXCR4/metabolismo , Relação Estrutura-AtividadeRESUMO
Candida antarctica lipase B has been used to kinetically resolve a structurally diverse series of bicyclic 1-heteroaryl primary amines by enantioselective acetylation. High yields of either enantiomer could be obtained with excellent enantioselectivity (90-99% ee), while the undesired enantiomer could, in some cases, be recycled by thermal racemization. The absolute stereochemistry of the products was confirmed by an X-ray crystal structure.
Assuntos
Aminas , Lipase/metabolismo , Acetilação , Aminas/análise , Aminas/química , Aminas/metabolismo , Catálise , Cristalografia por Raios X , Proteínas Fúngicas , Indicadores e Reagentes , Cinética , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , EstereoisomerismoRESUMO
A method to prepare amino-substituted 5,6,7,8-tetrahydroquinolines and 5,6,7,8-tetrahydroisoquinolines via catalytic hydrogenation of the corresponding acetamido-substituted quinolines and isoquinolines followed by acetamide hydrolysis is described. The yields of the products are good when the acetamido substituent is present on the pyridine ring and moderate with the acetamido substituent on the benzene ring. This method has also been applied to the regioselective reduction of quinoline substrates bearing other substituents (R = OMe, CO(2)Me, Ph).