N-aryl-piperidine-4-carboxamides as a novel class of potent inhibitors of MALT1 proteolytic activity.

Bioorg Med Chem Lett 2018 07 9;28(12):2153-2158. Epub 2018 May 9.

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

Starting from a weak screening hit, potent and selective inhibitors of the MALT1 protease function were elaborated. Advanced compounds displayed high potency in biochemical and cellular assays. Compounds showed activity in a mechanistic Jurkat T cell activation assay as well as in the B-cell lymphoma line OCI-Ly3, which suggests potential use of MALT1 inhibitors in the treatment of autoimmune diseases as well as B-cell lymphomas with a dysregulated NF-κB pathway. Initially, rat pharmacokinetic properties of this compound series were dominated by very high clearance which could be linked to amide cleavage. Using a rat hepatocyte assay a good in vitro-in vivo correlation could be established which led to the identification of compounds with improved PK properties.

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Source
https://linkinghub.elsevier.com/retrieve/pii/S0960894X183041
Publisher Site
http://dx.doi.org/10.1016/j.bmcl.2018.05.017DOI Listing
July 2018

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