Discovery of Novel 2-Morpholine Tetrahydroisoquinoline CXCR4 Antagonists with Unique Properties

The exploration of tetrahydroisoquinoline-based CXCR4 antagonists as therapeutics is described. Starting from TIQ-15, halogen and heterocycle derivatives led to the identification of the 2-position N-morpholine. The initial compounds, 28 and 42, had significant improvements in CYP 2D6 inhibition and PAMPA permeability while maintaining CXCR4 potency. These were evaluated in a mouse pharmacokinetic (PK) study, exhibiting low oral bioavailability. In a second round of medicinal chemistry, the N-methyl derivative 45 provided surprisingly good CXCR4 potency. The compound had high permeability, modest metabolic stability, and CYP 2D6 inhibition, with a high hERG therapeutic index (TI) and improved exposure when dosed orally to mice. Subsequently, extensive changes to the morpholine ring of 45 led to compounds 75 and 81, which provided potent CXCR4 activity, high permeability, good selectivity against CYP 2D6, and a high hERG TI. Pharmacokinetic studies in mice for 75 and 81 showed similar improvements to 45 in exposure after oral dosing.