4 research outputs found
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 (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 Cmax 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
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 (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 Cmax 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
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 (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 Cmax 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
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 (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 Cmax 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