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
  • 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.
Products