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

ACS Med Chem Lett 2018 Apr 20;9(4):392-396. Epub 2018 Mar 20.

Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.

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.

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Source
http://dx.doi.org/10.1021/acsmedchemlett.8b00098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900337PMC
April 2018

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