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.

本研究阐述了以四氢异喹啉（tetrahydroisoquinoline）为骨架的CXCR4拮抗剂作为治疗药物的探索历程。以TIQ-15为起始化合物，通过卤素与杂环衍生物修饰，最终确定了2位N-吗啉基取代的修饰策略。初始化合物28与42在细胞色素P450 2D6（CYP 2D6）抑制活性与平行人工膜渗透性测定（PAMPA）渗透性方面获得显著改善，同时保留了对CXCR4的抑制活性。随后对二者开展小鼠药代动力学（PK）研究，结果显示其口服生物利用度较低。在第二轮药物化学优化工作中，N-甲基取代衍生物45展现出了优异的CXCR4抑制活性。该化合物具备高膜渗透性、适度的代谢稳定性与CYP 2D6抑制活性，同时拥有较高的hERG治疗指数（TI），且小鼠口服给药后的体内暴露量得到提升。后续通过对45的吗啉环进行大范围结构修饰，得到化合物75与81：二者均具备强效的CXCR4抑制活性、高膜渗透性，对CYP 2D6具备良好的选择性，且拥有较高的hERG治疗指数。对75与81开展的小鼠药代动力学研究显示，其口服给药后的体内暴露量与45相比获得了类似的改善。