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 CXCR44(+) 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.