2. Academic Validation
  3. Discovery of N-Alkyl Piperazine Side Chain Based CXCR4 Antagonists with Improved Drug-like Properties

Discovery of N-Alkyl Piperazine Side Chain Based CXCR4 Antagonists with Improved Drug-like Properties

  • ACS Med Chem Lett. 2018 Apr 9;9(5):446-451. doi: 10.1021/acsmedchemlett.8b00030.
Yesim A Tahirovic 1,  Valarie M Truax 1,  Robert J Wilson 1,  Edgars Jecs 1,  Huy H Nguyen 1,  Eric J Miller 1,  Michelle B Kim 1,  Katie M Kuo 1,  Tao Wang 2,  Chi S Sum 2,  Mary E Cvijic 2,  Gretchen M Schroeder 2,  Lawrence J Wilson 1,  Dennis C Liotta 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
  • 2 Bristol-Myers Squibb R&D, US Route 206 and Province Line Road, Princeton, New Jersey 08543-4000, United States.
PMID: 29795757 DOI: 10.1021/acsmedchemlett.8b00030
Abstract

A novel series of CXCR4 antagonists with piperidinyl and piperazinyl alkylamine side chains designed as butyl amine replacements are described. Several of these compounds showed similar activity to the parent compound TIQ-15 (5) in a SDF-1 induced calcium flux assay. Preliminary structure-activity relationship investigations led us to identify a series containing N-propyl piperazine side chain analogs exemplified by 16 with improved off-target effects as measured in a Muscarinic Acetylcholine Receptor (mAChR) calcium flux assay and in a limited drug safety panel screen. Further efforts to explore SAR and optimize drug properties led to the identification of the N'-ethyl-N-propyl-piperazine tetrahydroisoquinoline derivative 44 and the N-propyl-piperazine benzimidazole compound 37, which gave the best overall profiles with no mAChR or CYP450 inhibition, good permeability in PAMPA assays, and metabolic stability in human liver microsomes.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-115493
    CXCR4 Antagonist