Design, Synthesis, and Pharmacological Evaluation of Second-Generation Tetrahydroisoquinoline-Based CXCR4 Antagonists with Favorable ADME Properties

CXCR4 is a G-protein-coupled
receptor that interacts with its cognate
ligand, CXCL12, to synchronize many physiological responses and pathological
processes. Disruption of the CXCL12–CXCR4 circuitry by small-molecule
antagonists has emerged as a promising strategy for cancer intervention.
We previously disclosed a hit-to-lead effort that led to the discovery
of a series of tetrahydroisoquinoline-based CXCR4 antagonists exemplified
by the lead compound TIQ15. Herein, we describe our medicinal-chemistry
efforts toward the redesign of TIQ15 as a result of high mouse-microsomal
clearance, potent CYP2D6 inhibition, and poor membrane permeability.
Guided by the in vitro ADME data of TIQ15, structural modifications
were executed to provide compound 12a, which demonstrated
a reduced potential for first-pass metabolism while maintaining CXCR4
potency. Subsequent SAR studies and multiparameter optimization of 12a resulted in the identification of compound 25o, a highly potent, selective, and metabolically stable CXCR4 antagonist
possessing good intestinal permeability and low risk of CYP-mediated
drug–drug interactions.