Harnessing dual-mode RIPK1 ligands for cross-species anti-necroptosis inhibitor compounds

[Display omitted] •Synthesis and biological evaluation of novel mixed type RIPK1 inhibitors.•Installation of a rigid acetylene moiety enhanced the activity.•Our inhibitor showed promising in vivo results. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) has a crucial role in cell death and inflammation. A promising approach to develop novel inhibitors of RIPK1 mediated necroptosis is to mix the different binding modes of the known RIPK1 inhibitors into one molecule. Herein we report the synthesis and biological evaluation of novel mixed type inhibitors. Using Eclitasertib as a starting point, and applying our previous, published knowledge regarding cyclic malonamides, we successfully identified a library of active compounds. The active enantiomer of the most balanced and promising compound was subjected to pharmacokinetics and in vivo hypothermia study in mice.