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
The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.