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

• Published in: Bioorganic & medicinal chemistry letters 2018-07, Vol.28 (12), p.2153-2158
• Main Authors: Schlapbach, Achim, Revesz, Laszlo, Pissot Soldermann, Carole, Zoller, Thomas, Régnier, Catherine H., Bornancin, Frédéric, Radimerski, Thomas, Blank, Jutta, Schuffenhauer, Ansgar, Renatus, Martin, Erbel, Paulus, Melkko, Samu, Heng, Richard, Simic, Oliver, Endres, Ralf, Wartmann, Markus, Quancard, Jean
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Autoimmune disease; B-cell lymphoma; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Hepatocytes - drug effects; Humans; Jurkat Cells; MALT1; Microsomes - drug effects; Molecular Structure; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - antagonists & inhibitors; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - metabolism; Paracaspase; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Protease inhibitors; Proteolysis - drug effects; Rats; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.05.017

[Display omitted] •MALT1 plays a key role in NF-κB pathway activation.•A weak hit was optimized to potent and selective inhibitors of the MALT1.•Compounds show activity in several mechanistic cellular assays.•A good in vitro-in vivo correlation was established using a rat hepatocyte assay. 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.