发现、合成及鉴定一种可口服生物利用度、脑穿透的混合谱系激酶 3 抑制剂。

Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3.

机构信息

Califia Bio Inc. , 11575 Sorrento Valley Road, San Diego 92121, California, United States.

出版信息

J Med Chem. 2013 Oct 24;56(20):8032-48. doi: 10.1021/jm401094t. Epub 2013 Oct 3.

Inhibition of mixed lineage kinase 3 (MLK3) is a potential strategy for treatment of Parkinson's disease and HIV-1 associated neurocognitive disorders (HAND), requiring an inhibitor that can achieve significant brain concentration levels. We report here URMC-099 (1) an orally bioavailable (F = 41%), potent (IC50 = 14 nM) MLK3 inhibitor with excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels. The compound inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice. Compound 1 likely functions in HAND preclinical models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM). We compare the kinase specificity and BBB penetration of 1 with CEP-1347 (2). Compound 1 is well tolerated, with excellent in vivo activity in HAND models, and is under investigation for further development.

混合谱系激酶 3（MLK3）的抑制作用是治疗帕金森病和 HIV-1 相关神经认知障碍（HAND）的一种潜在策略，需要一种能够达到显著脑浓度水平的抑制剂。我们在此报告 URMC-099（1），这是一种口服生物利用度（F = 41%）、强效（IC50 = 14 nM）的 MLK3 抑制剂，在小鼠 PK 模型中具有出色的脑暴露，并且对关键的人细胞色素 P450 酶或 hERG 通道的干扰最小。该化合物抑制 LPS 诱导的小胶质细胞中 TNFα 的释放、HIV-1 Tat 诱导的人单核细胞中细胞因子的释放以及 Tat 注射小鼠脑中磷酸化 JNK 的上调。化合物 1 通过抑制包括 MLK3 和 LRRK2 在内的多种激酶途径，可能在 HAND 临床前模型中发挥作用（IC50 = 11 nM）。我们比较了 1 与 CEP-1347（2）的激酶特异性和 BBB 穿透性。化合物 1 具有良好的耐受性，在 HAND 模型中具有优异的体内活性，正在进一步开发中。