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

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Peng P,Chen H,Zhu Y,Wang Z,Li J,Luo RH,Wang J,Chen L,Yang LM,Jiang H,Xie X,Wu B,Zheng YT,Liu H

doi

10.1021/acs.jmedchem.8b01077

subject

Has Abstract

pub_date

2018-11-08 00:00:00

pages

9621-9636

issue

21

eissn

0022-2623

issn

1520-4804

journal_volume

61

pub_type

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