|
|
Structure-Based Design of 1-Heteroaryl-1,3-propanediamine Derivatives as a Novel Series of CC-Chemokine Receptor 5 Antagonists
|
author: |
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 |
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 ? 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
|
Contact the author: |
|
Page number: |
|
Issue: |
|
Subject: |
|
Authors units: |
|
PubYear: |
2018 |
Volume: |
|
Unit code: |
152453 |
Publication name: |
Journal of Medicinal Chemistry |
The full text link: |
Download |
Full papers: |
Download |
Departmens of first author: |
|
Paper source: |
https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01077 |
Paper type: |
|
Participation of the author: |
|
EMAIL: |
|
|