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 21, 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 36, which showed improved pharmacokinetic
properties in rats and dogs. Evaluation in the Lewis rat adjuvant-induced
arthritis model showed that compound 36 had a robust
inflammation inhibitory effect and joint repair ability. Currently,
compound 36 is being considered for preclinical development
as a potential treatment for inflammatory diseases.