Design, synthesis and biological evaluation of novel cyclic malonamide derivatives as selective RIPK1 inhibitors

Bioorg Med Chem Lett. 2024 Feb 3;100:129643. doi: 10.1016/j.bmcl.2024.129643. Online ahead of print.ABSTRACTReceptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a key role in cell death and inflammation. RIPK1 is a well-established therapeutic target, due to the presence of a unique kinase-regulating allosteric pocket, which enables selective inhibition. Herein we used GSK2982772 as our starting point in our discovery campaign. Applying isosteric replacement, we successfully identified the malonamide scaffold, instead of the well-established serine template. Further structural optimization led to the design and synthesis of a series of analog inhibitors. The enantiomers of the most promising compound were tested on 97 different kinases. The active enantiomer proved to be kinase selective.PMID:38316369 | DOI:10.1016/j.bmcl.2024.129643

Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2024 Category: Chemistry Authors: J ózsef Levente Petró Gyula B ényei P éter Bana Nikolett Linke Ferenc Horti Judit Eszter Szab ó Krisztina Katalin Szalai G ábor Hornyánszky Istv án Greiner J ános Éles Source Type: research