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Bioorg Med Chem Lett. 2015 Nov 1;25(21):4950-4955. doi: 10.1016/j.bmcl.2015.04.036. Epub 2015 Apr 17.

Discovery of novel N-aryl piperazine CXCR4 antagonists.

Author information

1
Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, GA 30329, United States.
2
Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, GA 30322, United States.
3
Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, GA 30329, United States; Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, GA 30322, United States.
4
Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, GA 30322, United States. Electronic address: ljwilso@emory.edu.

Abstract

A novel series of CXCR4 antagonists with substituted piperazines as benzimidazole replacements is described. These compounds showed micromolar to nanomolar potency in CXCR4-mediated functional and HIV assays, namely inhibition of X4 HIV-1(IIIB) virus in MAGI-CCR5/CXCR4 cells and inhibition of SDF-1 induced calcium release in Chem-1 cells. Preliminary SAR investigations led to the identification of a series of N-aryl piperazines as the most potent compounds. Results show SAR that indicates type and position of the aromatic ring, as well as type of linker and stereochemistry are significant for activity. Profiling of several lead compounds showed that one (49b) reduced susceptibility towards CYP450 and hERG, and the best overall profile when considering both SDF-1 and HIV potencies (6-20 nM).

KEYWORDS:

CXC chemokine receptor 4; CXCR4 antagonists; G-protein coupled receptor; HIV; Piperazine

PMID:
25935642
PMCID:
PMC5776727
DOI:
10.1016/j.bmcl.2015.04.036
[Indexed for MEDLINE]
Free PMC Article

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