Modulating ADME Properties by Fluorination: MK2 Inhibitors with Improved Oral Exposure,ACS Medicinal Chemistry Letters

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Modulating ADME Properties by Fluorination: MK2 Inhibitors with Improved Oral Exposure
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-03-20 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00098
Juraj Velcicky ₁ , Achim Schlapbach ₁ , Richard Heng ₁ , Laszlo Revesz ₁ , Daniel Pflieger ₁ , Ernst Blum ₁ , Stuart Hawtin ₁ , Christine Huppertz ₁ , Roland Feifel ₁ , Rene Hersperger ₁

Affiliation

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 in vivo clearance leading to significantly increased oral exposure.

中文翻译：

通过氟化调节ADME特性：改善口腔暴露的MK2抑制剂

MAP激活的蛋白激酶2（MK2）在调节先天免疫应答以及DNA损伤后的细胞存活中起着重要作用。尽管具有治疗炎症和癌症的潜力，但迄今为止，尚未有MK2低分子量抑制剂进入临床，这主要是由于吸收，分布，代谢和排泄（ADME）性能不足所致。我们在这里描述一种方法，该方法基于在最近描述的基于吡咯的MK2抑制剂支架中专门放置的氟来操纵其理化和ADME特性。在保持靶标效力的同时，新型氟衍生物显示出大大改善的渗透性以及增强的溶解度和降低的体内清除率，从而导致口腔暴露量显着增加。

更新日期：2018-03-20

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