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

Journal of Medicinal Chemistry
Panfeng PengHong Liu

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.

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Citations

Feb 6, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Fedora GrandeAntonio Garofalo
Jun 19, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Michele MontaruliOrazio Nicolotti
Jul 4, 2019·Molecular Pharmacology·Marta ArimontRob Leurs
Oct 13, 2019·Protein Science : a Publication of the Protein Society·Ram Prasad BhusalMartin J Stone
Jun 18, 2021·Science Advances·Polina IsaikinaStephan Grzesiek
Apr 17, 2019·The Journal of Organic Chemistry·Anton V ChernykhOleksandr O Grygorenko
Sep 28, 2021·Journal of Biomolecular Structure & Dynamics·Patrick Appiah-KubiMahmoud E S Soliman

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