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.