RESUMO
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.
Assuntos
Fármacos Anti-HIV/farmacologia , Benzoatos/farmacologia , Antagonistas dos Receptores CCR5 , Replicação Viral/efeitos dos fármacos , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Benzoatos/síntese química , Benzoatos/química , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cricetinae , Cricetulus , Desenho de Fármacos , Células HEK293 , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Imidazolidinas/química , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Modelos Químicos , Estrutura Molecular , Piperidinas/química , Receptores CCR5/genética , Receptores CCR5/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels.
RESUMO
Based on the attrition rate of CCR5 small molecule antagonists in the clinic the discovery and development of next generation antagonists with an improved pharmacology and safety profile is necessary. Herein, we describe a combined molecular modeling, CCR5-mediated cell fusion, and receptor site-directed mutagenesis approach to study the molecular interactions of six structurally diverse compounds (aplaviroc, maraviroc, vicriviroc, TAK-779, SCH-C and a benzyloxycarbonyl-aminopiperidin-1-yl-butane derivative) with CCR5, a coreceptor for CCR5-tropic HIV-1 strains. This is the first study using an antifusogenic assay, a model of the interaction of the gp120 envelope protein with CCR5. This assay avoids the use of radioactivity and HIV infection assays, and can be used in a high throughput mode. The assay was validated by comparison with other established CCR5 assays. Given the hydrophobic nature of the binding pocket several binding models are suggested which could prove useful in the rational drug design of new lead compounds.