9Th Brazilian Symposium on Medicinal Chemistry

In the past years our group has been investigating the LINS01 compounds as H3R/H4R antagonists, leading to molecules with promising in vivo activity. However, key questions about the SAR of such compounds were raised. Therefore, docking studies of the LINS01 compounds were done on H3R/H4R homology models. The dockings were performed on Glide software with MD simulations and suggested that the LINS01 compounds may interact in similar fashion as the prototypes ABT-239 (H3R) and JNJ-7777120 (H4R). The results indicated that chirality seems not important to the binding of LINS01 compounds. The poses also suggested that a phenyl group in the dihydrobenzofuran would improve the activity; thus LINS01016 was synthesized, showing high affinity (H3R IC50=116 nM). Additionally, the synthesized benzofurancarboxamide LINS01018 (H4R IC50=352 nM) also confirmed the docking suggestion. In summary, this work is an outstanding example of the synergy between CADD and experimental results to achieve high affinity molecules.