RESUMO
Truncation of the original piperidino-2(S)-methyl piperazine lead structure 2, from a family of muscarinic antagonists, gave compound 8 which has improved selectivity for the HIV-1 co-receptor CCR5 over muscarinic receptors. Further optimization for pharmacokinetic properties afforded Sch-350634 (1), a prototypical piperazine-based CCR5 antagonist, which is a potent inhibitor of HIV-1 entry and replication in PBMCs. The title compound (1) has excellent oral bioavailability in rat, dog, and monkey.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Óxidos N-Cíclicos/síntese química , Piperazinas/síntese química , Administração Oral , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Disponibilidade Biológica , Linhagem Celular , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacocinética , Óxidos N-Cíclicos/farmacologia , Cães , HIV-1/efeitos dos fármacos , Técnicas In Vitro , Leucócitos Mononucleares/virologia , Macaca fascicularis , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Optimization of the piperidino-piperazines 1 and 2 provided early leads 3 and 4, which showed good activity in the CCR5-RANTES binding assay and in antiviral assays. A systematic study around these structures showed that the 2(S)-methyl piperazine is essential for CCR5 affinity, which is further enhanced by forming the 2,6-dimethyl benzamide of the piperidine.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Piperazinas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Testes de Sensibilidade Microbiana , Piperazinas/química , Relação Estrutura-AtividadeRESUMO
The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.
Assuntos
Compostos de Benzilideno/química , Dioxóis/química , Dioxóis/farmacologia , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Sulfonas/química , Sulfonas/farmacologia , Acetilcolina/análise , Acetilcolina/metabolismo , Administração Oral , Animais , Área Sob a Curva , Compostos de Benzilideno/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Humanos , Macaca fascicularis , Microdiálise , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Antagonistas Muscarínicos/sangue , Ratos , Receptor Muscarínico M2 , Relação Estrutura-AtividadeRESUMO
Lawn mowing approximates 4 to 6 METs and may evoke heart rate and systolic blood pressure responses that approach and exceed those attained during maximal exercise testing. The excessive cardiac demands may be deceptively camouflaged by the moderate aerobic requirements and perceived effort.
