RESUMO
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
The redesign of azamacrocyclic CXCR4 chemokine receptor antagonists resulted in the discovery of novel, small molecule, orally bioavailable compounds that retained T-tropic (CXCR4 using, X4) anti-HIV-1 activity. A structure-activity relationship (SAR) was determined on the basis of the inhibition of replication of X4 HIV-1 NL4.3 in MT-4 cells. As a result of lead optimization, we identified (S)-N'-((1H-benzo[d]imidazol-2-yl)methyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (AMD070) 2 as a potent and selective antagonist of CXCR4 with an IC(50) value of 13 nM in a CXCR4 125I-SDF inhibition binding assay. Compound 2 inhibited the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC(50) of 2 and 26 nM, respectively, while remaining noncytotoxic to cells at concentrations exceeding 23 microM. The pharmacokinetics of 2 was evaluated in rat and dog, and good oral bioavailability was observed in both species. This compound represents the first small molecule orally bioavailable CXCR4 antagonist that was developed for the treatment of HIV-1 infection.
