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

Abstract Starting from a weak screening hit, potent and selective inhibitors of the MALT1protease 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 lymphomaline OCI-Ly3, which suggests potential use of MALT1inhibitors in the treatment of autoimmune diseases as well as B-cell lymphomaswith 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.