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

J Med Chem. 2018 Nov 8;61(21):9621-9636. doi: 10.1021/acs.jmedchem.8b01077. Epub 2018 Oct 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Anti-HIV Agents / toxicity
  • CCR5 Receptor Antagonists / chemistry*
  • CCR5 Receptor Antagonists / pharmacology*
  • CCR5 Receptor Antagonists / toxicity
  • Cell Line
  • Diamines / chemistry*
  • Diamines / pharmacology*
  • Diamines / toxicity
  • Drug Design*
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Receptors, CCR5 / chemistry
  • Receptors, CCR5 / metabolism*


  • Anti-HIV Agents
  • CCR5 Receptor Antagonists
  • Diamines
  • Receptors, CCR5
  • trimethylenediamine