Optimization of the In Vivo Potency of Pyrazolopyrimidine MALT1 Protease Inhibitors by Reducing Metabolism and Increasing Potency in Whole Blood.

Basic Information

ID: ALA4699655

Journal: J Med Chem

Title: Optimization of the In Vivo Potency of Pyrazolopyrimidine MALT1 Protease Inhibitors by Reducing Metabolism and Increasing Potency in Whole Blood.

Authors: Quancard J,Simic O,Pissot Soldermann C,Aichholz R,Blatter M,Renatus M,Erbel P,Melkko S,Endres R,Sorge M,Kieffer L,Wagner T,Beltz K,Mcsheehy P,Wartmann M,Régnier CH,Calzascia T,Radimerski T,Bigaud M,Weiss A,Bornancin F,Schlapbach A

Abstract: The paracaspase MALT1 has gained increasing interest as a target for the treatment of subsets of lymphomas as well as autoimmune diseases, and there is a need for suitable compounds to explore the therapeutic potential of this target. Here, we report the optimization of the in vivo potency of pyrazolopyrimidines, a class of highly selective allosteric MALT1 inhibitors. High doses of the initial lead compound led to tumor stasis in an activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) xenograft model, but this compound suffered from a short in vivo half-life and suboptimal potency in whole blood. Guided by metabolism studies, we identified compounds with reduced metabolic clearance and increased in vivo half-life. In the second optimization step, masking one of the hydrogen-bond donors of the central urea moiety through an intramolecular interaction led to improved potency in whole blood. This was associated with improved in vivo potency in a mechanistic model of B cell activation. The optimized compound led to tumor regression in a CARD11 mutant ABC-DLBCL lymphoma xenograft model.

CiteXplore: 33216547

DOI: 10.1021/acs.jmedchem.0c01246

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