Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV-1 Activities and Improved Oral Bioavailability.

Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 antagonist approved by FDA; however, serious side effects limited its clinical use. Herein, 21 novel tropane derivatives () were designed and synthesized based on the CCR5-maraviroc complex structure. Among them, compounds and had comparable activity to maraviroc and presented more potent inhibitory activity against a series of HIV-1 strains. In addition, compound exhibited synergistic or additive antiviral effects in combination with other antiretroviral agents. Compared to maraviroc, both and displayed higher and AUC and improved oral bioavailability in SD rats. In addition, compounds and showed no significant CYP450 inhibition and showed a novel binding mode with CCR5 different from that of maraviroc-CCR5. In summary, compounds and are promising drug candidates for the treatment of HIV-1 infection.