Single-Dose Drug Development Candidate for Schistosomiasis
Aryl hydantoins were identified in the early 1980s as a promising antischistosomal chemotype. However, as exemplified by Ro 13-3978, this compound series produced antiandrogenic side effects on the host, a not unexpected outcome given their structural similarity to the antiandrogenic drug nilutamide. The two key advances in our optimization of Ro 13-3978 were swapping the aryl trifluoromethyl substituent with a difluoroethyl to abolish antiandrogenic effects and replacing the hydrogen atoms of the <i>gem</i>-dimethyl substructure with deuterium atoms to increase metabolic stability. Combining these two structural changes led to the discovery of single-dose drug candidate AR102, a compound with potent, selective, and broad-spectrum activity against schistosomes, a long pharmacokinetic half-life in preclinical species, and an acceptable safety profile.
Authors
- Jeremy O. Jones (ORCID: https://orcid.org/0000-0002-6080-8103)
- Jonathan L. Vennerstrom (ORCID: https://orcid.org/0000-0003-0075-2336)
- Michael J. Campbell (ORCID: https://orcid.org/0000-0003-3529-2739)
- Cécile Häberli (ORCID: https://orcid.org/0000-0002-1282-8070)
- Kasiram Katneni
- Derek A. Leas (ORCID: https://orcid.org/0000-0002-0190-543X)
- David M. Shackleford (ORCID: https://orcid.org/0000-0002-8229-6591)
- Yuxiang Dong (ORCID: https://orcid.org/0000-0003-1412-3178)
- Andrew J. Neville (ORCID: https://orcid.org/0000-0001-6237-9640)
- Paul H. Davis (ORCID: https://orcid.org/0000-0002-0526-3841)
- Susan A. Charman (ORCID: https://orcid.org/0000-0003-1753-8213)
- Thomas T. Schulze (ORCID: https://orcid.org/0000-0002-3597-5727)
- Rahul Patil (ORCID: https://orcid.org/0000-0003-0530-6933)
- Gong Chen (ORCID: https://orcid.org/0000-0002-1857-3670)
- Xiaofang Wang (ORCID: https://orcid.org/0000-0002-3568-8066)
- Thao Pham
- Jennifer Keiser
- Meiyu Hu
Institutions
- University of Nebraska at Omaha (US)
- City Of Hope National Medical Center (US)
- Nebraska Medical Center (US)
- Swiss Tropical and Public Health Institute (CH)
- University of Basel (CH)
- Bipar (FR)
- Monash University (AU)
- University of Nebraska Medical Center (US)
Publication Details
- Journal
- ACS Infectious Diseases
- Published
- 2024-10-18
- DOI
- https://doi.org/10.1021/acsinfecdis.4c00677
- Citations
- 3
- Primary Topic
- Parasites and Host Interactions
- Type
- article
- Field-Weighted Citation Impact
- 1.55
Funders
- Nebraska Space Grant Consortium
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases