Quancard, Jean, Simic, Oliver, Pissot Soldermann, Carole, aichholz, reiner, Blatter, Markus, Renatus, Martin, Erbel, Paulus, Melkko, Samu, Endres, Ralf, Sorge, Mickael, Kieffer, Laurence, Wagner, Beatrix, Beltz, Karen, mcsheehy, paul, Wartmann, Markus, Regnier, Catherine, Calzascia, Thomas, radimerski, thomas, Bigaud, Marc, Weiss, Andreas, Bornancin, Frederic and Schlapbach, Achim (2020) Optimization of the in vivo potency of pyrazolopyrimidine MALT1 protease inhibitors by reducing metabolism and increasing potency in whole blood. Journal of Medicinal Chemistry. ISSN 0022-26231520-4804

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. The initial lead compound led to tumor stasis at high doses in activated B-cell like(ABC) diffuse large B-cell lymphoma (DLBCL) xenograft model but 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 a second optimization step, masking one of the hydrogen bond donors of the central urea moiety through an intra-molecular interaction reduced unspecific binding. This improved potency in whole blood which 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.

Item Type:	Article
Date Deposited:	08 Dec 2020 00:45
Last Modified:	08 Dec 2020 00:45
URI:	https://oak.novartis.com/id/eprint/41994