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.