Synovial sarcoma is a malignant tumor of the soft tissues. Although it is clear that the SS18–SSX fusion protein generated by t(X;18)(p11.2;q11.2) drives synovial sarcoma, the underlying mechanism remains unknown, making drug discovery research difficult. However, it was recently reported that inhibition of histone deacetylase (HDAC) 2 leads to the degradation of SS18-SSX. Unfortunately, HDAC inhibitors usually inhibit multiple HDACs simultaneously, and there is only one example of an HDAC2-selective inhibitor. Therefore, the development of inhibitors with high isozyme selectivity would be valuable. In this study, we aimed to design small-molecule compounds with significant differences in binding affinity between HDAC1 and HDAC2, which have very high sequence identity. To achieve this aim, we performed molecular dynamics calculations, organic synthesis, measurement of dissociation kinetics, and measurement of growth-inhibitory effects on synovial sarcoma cells. The molecular dynamics calculations of the structures of HDAC1 and HDAC2 without drug revealed that the pocket volume of the drug binding site is clearly larger in HDAC2, suggesting that selective inhibitors could feasibly be developed. Based on the pocket volume revealed by MD pocket analysis, we are designing drugs with high affinity for HDAC2.