Structure–Activity Relationship of Antischistosomal Aryl Hydantoin (AR102)

As exemplified by Ro 13–3978 (1), aryl hydantoins were identified in the early 1980s as a promising antischistosomal chemotype. We now describe the structure–activity relationship (SAR) of this compound series, which led to the discovery of the drug development candidate AR102 (5). These aryl hydantoins had good in vitro ADME profiles, with calculated polar surface area (PSA) values of 49–87 Å, measured LogD7.4 values of 1.2–3.5, and aqueous kinetic solubilities of 25 to >100 μg/mL. The two key advances in our optimization of 1 were replacing the hydrogen atoms of the gem-dimethyl substructure with deuterium or fluorine atoms to slow Phase I metabolism and swapping the aryl trifluoromethyl substituent with difluoroethyl or difluoropropyl substituents to abolish antiandrogenic effects. There was no direct correlation between Cmax or AUC0‑last values and antischistosomal activity; however, with only one exception, compounds with the highest antischistosomal activities also had the highest exposures.