Discovery of novel N-aryl piperazine CXCR4 antagonists

Huanyu Zhao; Anthony R Prosser; Dennis C Liotta; Lawrence J Wilson

doi:10.1016/j.bmcl.2015.04.036

Discovery of novel N-aryl piperazine CXCR4 antagonists

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

Authors

Huanyu Zhao¹, Anthony R Prosser², Dennis C Liotta³, Lawrence J Wilson⁴

Affiliations

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cytochrome P-450 Enzyme Inhibitors / chemical synthesis
Cytochrome P-450 Enzyme Inhibitors / chemistry
Cytochrome P-450 Enzyme Inhibitors / pharmacology*
Cytochrome P-450 Enzyme System / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
Ether-A-Go-Go Potassium Channels / metabolism
Humans
Models, Molecular
Molecular Structure
Piperazine
Piperazines / chemical synthesis
Piperazines / chemistry
Piperazines / pharmacology*
Receptors, CXCR4 / antagonists & inhibitors*
Receptors, CXCR4 / metabolism
Structure-Activity Relationship

Substances

CXCR4 protein, human
Cytochrome P-450 Enzyme Inhibitors
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
KCNH2 protein, human
Piperazines
Receptors, CXCR4
Piperazine
Cytochrome P-450 Enzyme System

Grants and funding

R01 AI028731/AI/NIAID NIH HHS/United States