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

Schlapbach, Achim and Revesz, Laszlo and Pissot Soldermann, Carole and Zoller, Thomas and Regnier, Catherine and Bornancin, Frederic and Radimerski, Thomas and Blank, Jutta and Schuffenhauer, Ansgar and Renatus, Martin and Erbel, Paulus and Heng, Richard and Melkko, Samu and Simic, Oliver and Endres, Ralf and Wartmann, Markus and Quancard, Jean (2018) N-aryl-piperidine-4-carboxamides as a novel class of potent inhibitors of MALT1 proteolytic activity. Bioorganic and Medicinal Chemistry Letters, 28. pp. 2153-2158. ISSN 14643405

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.

Item Type: Article
Keywords: Autoimmune disease B-cell lymphoma MALT1 Paracaspase Protease inhibitors
Date Deposited: 19 Jun 2018 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/34971

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