Discovery of <i>N</i>‑Alkyl Piperazine Side Chain Based CXCR4 Antagonists with Improved Drug-like Properties

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 (<b>5</b>) in a SDF-1 induced calcium flux assay. Preliminary structure–activity relationship investigations led us to identify a series containing <i>N</i>-propyl piperazine side chain analogs exemplified by <b>16</b> 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 <i>N</i>′-ethyl-<i>N</i>-propyl-piperazine tetrahydroisoquinoline derivative <b>44</b> and the <i>N</i>-propyl-piperazine benzimidazole compound <b>37</b>, which gave the best overall profiles with no mAChR or CYP450 inhibition, good permeability in PAMPA assays, and metabolic stability in human liver microsomes

Synthesis of Novel Tetrahydroisoquinoline CXCR4 Antagonists with Rigidified Side-Chains

A structure–activity relationship study of potent TIQ15-derived CXCR4 antagonists is reported. In this investigation, the TIQ15 side-chain was constrained to improve its drug properties. The cyclohexylamino congener <b>15a</b> was found to be a potent CXCR4 inhibitor (IC₅₀ = 33 nM in CXCL12-mediated Ca²⁺ flux) with enhanced stability in liver microsomes and reduced inhibition of CYP450 (2D6). The improved CXCR4 antagonist <b>15a</b> has potential therapeutic application as a single agent or combinatory anticancer therapy

Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties

CXCR4 is a seven-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by ≥48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4⁺ tumor cells from immune surveillance and chemotherapeutic elimination by (1) stimulating prosurvival signaling and (2) recruiting CXCR4⁺ immunosuppressive leukocytes. Additionally, distant CXCL12-rich niches attract and support CXCR4⁺ metastatic growths. Accordingly, CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival signaling, recondition the CXCR4⁺ leukocyte infiltrate from immunosuppressive to immunoreactive, and inhibit CXCR4⁺ cancer cell metastasis. Current small molecule CXCR4 antagonists suffer from poor oral bioavailability and off-target liabilities. Herein, we report a series of novel tetrahydro­isoquinoline-containing CXCR4 antagonists designed to improve intestinal absorption and off-target profiles. Structure–activity relationships regarding CXCR4 potency, intestinal permeability, metabolic stability, and cytochrome P450 inhibition are presented