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

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Abstract
CC-chemokine receptor 5 (CCR5) is an attractive target to prevent the entry of HIV-1 into human host cells. Maraviroc is the only one CCR5 antagonist 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 and low cytotoxicity, 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 overcome the potential drug-drug interaction of maraviroc. Compound 34 represents a promising drug candidate for the HIV infection treatment.
Funding Information
  • Ministry of Science and Technology of the People's Republic of China (2014ZX10005-002, 2015CB910304, 2009ZX09501-029, 2012ZX09301001-007, 2012CB910704)
  • National Natural Science Foundation of China (21402226, 81102483, 81321092, 81620108027, 21632008, 91229205, 81102461)
  • Chinese Academy of Sciences (CASIMM0120161006, CASIMM0320163020)
  • China Marine Commonweal Research Project (201005022-5)

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