Discovery of a Novel p38α-MK2 Complex Inhibitor as a Potential Choice for Autoimmune Diseases

The p38α-MK2 signaling axis plays an important role in the inflammatory response of cells. Here, we carried out a series of optimizations on CDD-450, aiming to enhance inhibition of the p38α-MK2 complex and improve pharmacokinetic properties. First, the magic F strategy was utilized to obtain compound <b>21</b>, which displayed a 60-fold increase in tumor necrosis factor α inhibition and a 600-fold increase in interleukin-6 inhibition. Molecular dynamics simulations revealed insights into the binding mode of fluorinated molecules. Subsequently, introducing a methyl group and a fluorine group led to compound <b>36</b>, which showed improved pharmacokinetic properties in rats and dogs. Evaluation in the Lewis rat adjuvant-induced arthritis model showed that compound <b>36</b> had a robust inflammation inhibitory effect and joint repair ability. Currently, compound <b>36</b> is being considered for preclinical development as a potential treatment for inflammatory diseases.