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

Abstract

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 (6–26) were designed and synthesized based on the CCR5-maraviroc complex structure. Among them, compounds 25 and 26 had comparable activity to maraviroc and presented more potent inhibitory activity against a series of HIV-1 strains. In addition, compound 26 exhibited synergistic or additive antiviral effects in combination with other antiretroviral agents. Compared to maraviroc, both 25 and 26 displayed higher C max and AUC0–∞ and improved oral bioavailability in SD rats. In addition, compounds 25 and 26 showed no significant CYP450 inhibition and showed a novel binding mode with CCR5 different from that of maraviroc-CCR5. In summary, compounds 25 and 26 are promising drug candidates for the treatment of HIV-1 infection.

Antiviral Protein–Protein Interaction Inhibitors

“…Recently, the structure of the CCR5-maraviroc complex ( Figure 9 ) was used for the design and synthesis of novel tropane derivatives. 91 Two of them, compounds 26 and 25 ( Figure 6 ), showed activity comparable to maraviroc, without significant cytochrome P450 (CYP450) inhibition. Furthermore, docking analysis of these compounds showed a new binding mode with CCR5 in comparison to maraviroc-CCR5, which implies that this could be a strategy to overcome the problem of drug resistance derived from maraviroc.…”

“…Recently, the structure of the CCR5-maraviroc complex (Figure ) was used for the design and synthesis of novel tropane derivatives . Two of them, compounds 26 and 25 (Figure ), showed activity comparable to maraviroc, without significant cytochrome P450 (CYP450) inhibition.…”