Discovery of a novel series of selective macrocyclic PKCTheta inhibitors

Bioorg Med Chem Lett. 2024 Feb 1;100:129630. doi: 10.1016/j.bmcl.2024.129630. Online ahead of print.ABSTRACTA series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed. In particular, it has been found that methyl substitutions on the linker can have a profound influence on both potency and metabolic stability. Several compounds showing very good profiles, suitable for in vivo testing, are disclosed.PMID:38307441 | DOI:10.1016/j.bmcl.2024.129630

Source: Bioorganic and Medicinal Chemistry Letters - February 2, 2024 Category: Chemistry Authors: Stefano Crosignani Sebastien Campos Claire Bouix-Peter Craig Harris Eric Talbot Haiyang Hu Shun Wang John Maclean Ugo Zanelli Simon Taylor Kevin Foote Feriel Hacini-Rachinel Edwige Nicodeme Valerie Julia Source Type: research