Discovery of\na Novel p38α-MK2 Complex Inhibitor\nas a Potential Choice for Autoimmune Diseases

The p38α-MK2 signaling axis plays an important\nrole in the\ninflammatory response of cells. Here, we carried out a series of optimizations\non CDD-450, aiming to enhance inhibition of the p38α-MK2 complex\nand improve pharmacokinetic properties. First, the magic F strategy\nwas utilized to obtain compound <b>21</b>, which displayed a\n60-fold increase in tumor necrosis factor α inhibition and a\n600-fold increase in interleukin-6 inhibition. Molecular dynamics\nsimulations revealed insights into the binding mode of fluorinated\nmolecules. Subsequently, introducing a methyl group and a fluorine\ngroup led to compound <b>36</b>, which showed improved pharmacokinetic\nproperties in rats and dogs. Evaluation in the Lewis rat adjuvant-induced\narthritis model showed that compound <b>36</b> had a robust\ninflammation inhibitory effect and joint repair ability. Currently,\ncompound <b>36</b> is being considered for preclinical development\nas a potential treatment for inflammatory diseases.