Bioisosteric Replacement of Arylamide-Linked Spine Residues with N-Acylhydrazones and Selenophenes as a Design Strategy to Novel Dibenzosuberone Derivatives as Type I 1/2 p38α MAP Kinase Inhibitors

Abstract

The recent disclosure of type I1/2 inhibitors for p38 MAPK demonstrated how the stabilization of the R-spine can be used as a strategy to greatly increase the target residence time (TRT) of inhibitors. Herein, we describe first time n-acylhydrazone and selenophene residues as spine-motives, yielding metabolically stable inhibitors with high potency on enzymatic, Nano-BRET and whole blood assays, improved metabolic stability and long TRT.