Amino-Heterocycle Tetrahydroisoquinoline CXCR4 Antagonists with Improved ADME Profiles via Late-Stage Buchwald Couplings.

This work surveys a variety of diamino-heterocycles as an isosteric replacement for the piperazine substructure of our previously disclosed piperarinyl-tetrahydroisoquinoline containing CXCR4 antagonists. A late-stage Buchwald coupling route was developed for rapid access to final compounds from commercial building blocks. Among 13 analogs in this study, compound embodying an aza-piperazine linkage was found to have the best overall profile with potent CXCR4 inhibitory activity and favorable in vitro absorption, distribution, metabolism, and excretion (ADME) properties. An analysis of the calculated physiochemical parameters (ROF, cLogD) and the experimental ADME attributes of the analogs lead to the selection of for pharmacokinetic studies in mice. Compared with the clinical compound AMD11070, compound has no CYP450 3A4 or 2D6 inhibition, higher metabolic stability and PAMPA permeability, greatly improved physiochemical parameters, and superior oral bioavailability (% = 24). A binding rationale for within CXCR4 was elucidated from docking and molecular simulation studies.