Work

Single-Dose Drug Development Candidate for Schistosomiasis

Year: 2024

Type: article

Abstract: 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 gem -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.

Source: ACS Infectious Diseases

DOI: 10.1021/acsinfecdis.4c00677

Authors: Derek A. Leas, Jennifer Keiser, Susan A. Charman, David M. Shackleford, Jeremy O. Jones, Michael Campbell, Gong Chen, Kasiram Katneni, Rahul Patil, Meiyu Hu, Thao Pham, Cécile Häberli, Thomas T. Schulze, Andrew J. Neville, Xiaofang Wang, Yuxiang Dong, Paul H. Davis, Jonathan L. Vennerstrom

Institutions: Nebraska Medical Center, University of Nebraska Medical Center, Swiss Tropical and Public Health Institute, University of Basel, Monash University, City Of Hope National Medical Center, Beckman Research Institute, University of Nebraska at Omaha

Language: English

Topic: Parasites and Host Interactions

Subfield: Parasitology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

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

Awards: G1165699202, G2318527552, G2902573628, G4645427207, Increasing the Antischistosomal Selectivity of Aryl Hydantoins, Optimization of Antischistosomal Chemotypes, Drug discovery and development for schistosomiasis: From repositioning of antimalarial drug leads and clinical advanced drug candidates to the development of a new paediatric formulation of praziquantel, Nebraska Research Network in Functional Genomics, G880118091

OpenAlex ID: W4403529666

FWCI: 1.073

Cites: 41

Cited by: 3

Related to: 10