Velcicky Juraj, Schlapbach Achim, Heng Richard, Revesz Laszlo, Pflieger Daniel, Blum Ernst, Hawtin Stuart, Huppertz Christine, Feifel Roland, Hersperger Rene
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
ACS Med Chem Lett. 2018 Mar 20;9(4):392-396. doi: 10.1021/acsmedchemlett.8b00098. eCollection 2018 Apr 12.
MAP-activated protein kinase 2 (MK2) plays an important role in the regulation of innate immune response as well as in cell survival upon DNA damage. Despite its potential for the treatment of inflammation and cancer, to date no MK2 low molecular weight inhibitors have reached the clinic, mainly due to inadequate absorption, distribution, metabolism, and excretion (ADME) properties. We describe here an approach based on specifically placed fluorine within a recently described pyrrole-based MK2 inhibitor scaffold for manipulation of its physicochemical and ADME properties. While preserving target potency, the novel fluoro-derivatives showed greatly improved permeability as well as enhanced solubility and reduced clearance leading to significantly increased oral exposure.
丝裂原活化蛋白激酶2（MK2）在先天性免疫反应的调节以及DNA损伤后的细胞存活中起着重要作用。尽管其具有治疗炎症和癌症的潜力，但迄今为止，尚无MK2低分子量抑制剂进入临床，主要原因是吸收、分布、代谢和排泄（ADME）特性不足。我们在此描述一种基于在最近描述的吡咯基MK2抑制剂支架中特定位置引入氟的方法，以操纵其物理化学和ADME特性。在保持靶点活性的同时，新型氟衍生物显示出显著提高的渗透性以及增强的溶解性和降低的清除率，从而导致口服暴露显著增加。
