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.