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

Velcicky, Juraj and Schlapbach, Achim and Heng, Richard and Revesz, Laszlo and Pflieger, Daniel and Blum, Ernst and Huppertz, Christine and Feifel, Roland and Hersperger, Rene (2018) Modulating ADME Properties by Fluorination: MK2 Inhibitors with Improved Oral Exposure. ACS Medicinal Chemistry Letters, 9 (4). pp. 392-396. ISSN 1948-58751948-5875

Abstract

MK2, MAP-activated protein kinase 2, plays an important role in the regulation of innate immune response as well as in cell survival upon DNA damage. Despite its potential in the treatment of inflammation and cancer, up to date no MK2 low molecular weight inhibitor reached the clinic, mainly because of inadequate ADME properties of the developed inhibitors. In this paper we describe 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 keeping the target potency, the novel fluoro-derivatives showed not only improved permeability but also enhanced solubility and reduced in vivo clearance leading to significantly increased oral exposure.

Item Type: Article
Keywords: MK2, fluorine, permeability, ADME properties, pharmacokinetic, directed ortho metalation
Date Deposited: 26 Apr 2018 00:45
Last Modified: 26 Apr 2018 00:45
URI: https://oak.novartis.com/id/eprint/35446

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