2. Academic Validation
  3. Single-Dose Drug Development Candidate for Schistosomiasis

Single-Dose Drug Development Candidate for Schistosomiasis

  • ACS Infect Dis. 2024 Oct 18. doi: 10.1021/acsinfecdis.4c00677.
Derek A Leas 1,  Jennifer Keiser 2 3,  Susan A Charman 4,  David M Shackleford 4,  Jeremy O Jones 5,  Michael Campbell 4,  Gong Chen 4,  Kasiram Katneni 4,  Rahul Patil 4,  Meiyu Hu 4,  Thao Pham 4,  Cécile Häberli 2 3,  Thomas T Schulze 6 7,  Andrew J Neville 6,  Xiaofang Wang 1,  Yuxiang Dong 1,  Paul H Davis 6,  Jonathan L Vennerstrom 1
Affiliations

Affiliations

  • 1 College of Pharmacy, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska 986125, United States.
  • 2 Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, Basel CH-4002, Switzerland.
  • 3 University of Basel, Basel CH-4003, Switzerland.
  • 4 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • 5 Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 93534-7059, United States.
  • 6 Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska 68198-6125, United States.
  • 7 Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, Nebraska 68198-6125, United States.
PMID: 39423362 DOI: 10.1021/acsinfecdis.4c00677
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.

Keywords

antiandrogenic; antischistosomal; aryl hydantoin; structure−activity relationship.

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