Pyridine Fluorination Technology 2018

Pyridine Fluorination @ MK2 Inhibitor Discovery with Improved Oral Exposure

 

 

Juraj Velcicky* , Achim Schlapbach, Richard Heng, Laszlo Revesz, Daniel Pflieger, Ernst Blum, Stuart Hawtin, Christine Huppertz, Roland Feifel, and Rene Hersperger

 

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

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/acsmedchemlett.8b00098

Publication Date (Web): March 20, 2018

Copyright © 2018 American Chemical Society

*E-mail: juraj.velcicky@novartis.com.

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.

Keywords:

ADME properties; directed ortho metalation; fluorine; MK2; permeability; pharmacokinetic

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.8b00098.

• Description of in vitro assays, pharmacokinetic measurements, synthesis procedures and characterization data for all compounds, and UPLC and NMR charts (PDF)

View: ACS ActiveView PDF | PDF | PDF w/ Links | Full Text HTML

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  • ml8b00098_si_001.pdf (987.69 kB)

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