Discovery of novel N-aryl piperazine CXCR4 antagonists.
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).
Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, GA 30329, United States.
Huanyu
H
Zhao
Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, GA 30322, United States.
Anthony R
AR
Prosser
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.
Dennis C
DC
Liotta
Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, GA 30322, United States. Electronic address: ljwilso@emory.edu.
Lawrence J
LJ
Wilson
D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
C527276:CXCR4 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010879:Piperazines; D019718:Receptors, CXCR4; D000077489:Piperazine; D003577:Cytochrome P-450 Enzyme System
CXC chemokine receptor 4; CXCR4 antagonists; G-protein coupled receptor; HIV; Piperazine