Single-Dose Drug Development Candidate for Schistosomiasis.

Autor: Leas DA; College of Pharmacy, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska 986125, United States., Keiser J; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, Basel CH-4002, Switzerland.; University of Basel, Basel CH-4003, Switzerland., Charman SA; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Shackleford DM; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Jones JO; Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 93534-7059, United States., Campbell M; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Chen G; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Katneni K; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Patil R; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Hu M; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Pham T; Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia., Häberli C; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, Basel CH-4002, Switzerland.; University of Basel, Basel CH-4003, Switzerland., Schulze TT; Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska 68198-6125, United States.; Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, Nebraska 68198-6125, United States., Neville AJ; Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska 68198-6125, United States., Wang X; College of Pharmacy, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska 986125, United States., Dong Y; College of Pharmacy, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska 986125, United States., Davis PH; Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska 68198-6125, United States., Vennerstrom JL; College of Pharmacy, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska 986125, United States.
Jazyk: angličtina
Zdroj: ACS infectious diseases [ACS Infect Dis] 2024 Nov 08; Vol. 10 (11), pp. 3963-3972. Date of Electronic Publication: 2024 Oct 18.
DOI: 10.1021/acsinfecdis.4c00677
Abstrakt: 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.
Databáze: MEDLINE