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ACS medicinal chemistry letters
Apr 12, 2018;9 (4): 392-396.

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

Juraj Velcicky, Achim Schlapbach, Richard Heng, Laszlo Revesz, Daniel Pflieger, Ernst Blum, Stuart Hawtin, Christine Huppertz, Roland Feifel, Rene Hersperger
Author Information
  1. Juraj Velcicky: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  2. Achim Schlapbach: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  3. Richard Heng: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  4. Laszlo Revesz: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  5. Daniel Pflieger: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  6. Ernst Blum: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  7. Stuart Hawtin: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  8. Christine Huppertz: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  9. Roland Feifel: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  10. Rene Hersperger: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
PMID: 29670707 DOI: 10.1021/acsmedchemlett.8b00098

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 clearance leading to significantly increased oral exposure.

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