Structure-Based Design of 1‑Heteroaryl-1,3-propanediamine Derivatives as a Novel Series of CC-Chemokine Receptor 5 Antagonists

CC-chemokine receptor 5 (CCR5) is
an attractive target for preventing
the entry of human immunodeficiency virus 1 (HIV-1) into human host
cells. Maraviroc is the only CCR5 antagonist, and it was marketed
in 2007. To overcome the shortcomings of maraviroc, structure-based
drug design was performed to minimize CYP450 inhibition and to enhance
anti-HIV potency and bioavailability. Thirty-four novel 1-heteroaryl-1,3-propanediamine
derivatives (1–34) were synthesized,
displaying CCR5-antagonist activities in the 2.3–296.4 nM range.
Among these, compounds 21 and 34 were the
most potent CCR5 antagonists, with excellent in vitro anti-HIV-1 activity,
low cytotoxicity, and an acceptable pharmacokinetic profile. Furthermore,
the X-ray crystal structures of compounds 21 and 34 bound to CCR5 were determined at 2.8 Å resolution.
Compound 34 exhibited no CYP450-inhibition activity at
25 μM, which overcomes the potential drug–drug interaction
of maraviroc. Compound 34 represents a promising drug
candidate for HIV-infection treatment.