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Modulating ADME Properties by Fluorination: MK2 Inhibitors with Improved Oral Exposure.

ABSTRACT: 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.

SUBMITTER: Velcicky J

PROVIDER: S-EPMC5900337 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Modulating ADME Properties by Fluorination: MK2 Inhibitors with Improved Oral Exposure.

Velcicky Juraj J Schlapbach Achim A Heng Richard R Revesz Laszlo L Pflieger Daniel D Blum Ernst E Hawtin Stuart S Huppertz Christine C Feifel Roland R Hersperger Rene R

ACS medicinal chemistry letters 20180320 4

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 i ...[more]

PMID: 29670707

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