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

Bioorganic & Medicinal Chemistry Letters
Achim SchlapbachJean Quancard

Abstract

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.

Citations

Jan 30, 2019·Nature Chemical Biology·Jean QuancardChristopher M Overall
Jan 26, 2020·Proceedings of the National Academy of Sciences of the United States of America·Rebekka SchairerMargot Thome
Jan 7, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Joo-Eun LeeHee Min Yoo
Jul 3, 2021·Expert Opinion on Therapeutic Patents·Isabel HampDaniel Krappmann
Dec 1, 2020·Journal of Medicinal Chemistry·Carole Pissot SoldermannCatherine H Régnier

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