Synthetic study of VLA-4/VCAM-1 inhibitors: Synthesis and structure–activity relationship of piperazinylphenylalanine derivatives

To improve poor pharmacokinetic characters of the preceding VLA-4 inhibitors, novel piperazinylphenylalanine derivatives were designed and optimized for oral bioavailability. To improve the poor pharmacokinetic characteristics of VLA-4 inhibitors, novel piperazinylphenylalanine derivatives were designed. This structure is expected to improve physicochemical properties by increasing overall basicity. By changing components at the 4-position of piperazine and the terminal group of the amido bond, 12t was found to be the most potent of this series of compounds. In addition, dichlorobenzoyl derivative 12aa exhibited better oral availability and showed efficacy in an in vivo model after oral administration.