Single-Dose\nDrug Development Candidate for Schistosomiasis

Aryl hydantoins were identified in the early 1980s as\na promising\nantischistosomal chemotype. However, as exemplified by Ro 13-3978,\nthis compound series produced antiandrogenic side effects on the host,\na not unexpected outcome given their structural similarity to the\nantiandrogenic drug nilutamide. The two key advances in our optimization\nof Ro 13-3978 were swapping the aryl trifluoromethyl substituent with\na difluoroethyl to abolish antiandrogenic effects and replacing the\nhydrogen atoms of the <i>gem</i>-dimethyl substructure with\ndeuterium atoms to increase metabolic stability. Combining these two\nstructural changes led to the discovery of single-dose drug candidate\nAR102, a compound with potent, selective, and broad-spectrum activity\nagainst schistosomes, a long pharmacokinetic half-life in preclinical\nspecies, and an acceptable safety profile.