2. Academic Validation
  3. Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978)

Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978)

  • J Med Chem. 2016 Dec 8;59(23):10705-10718. doi: 10.1021/acs.jmedchem.6b01410.
Chunkai Wang 1,  Qingjie Zhao 1,  Mireille Vargas 2 3,  Jeremy O Jones 4,  Karen L White 5,  David M Shackleford 5,  Gong Chen 5,  Jessica Saunders 5,  Alice C F Ng 5,  Francis C K Chiu 5,  Yuxiang Dong 1,  Susan A Charman 5,  Jennifer Keiser 2 3,  Jonathan L Vennerstrom 1
Affiliations

Affiliations

  • 1 College of Pharmacy, University of Nebraska Medical Center , 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
  • 2 Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute , Socinstrasse 57, CH-4002 Basel, Switzerland.
  • 3 University of Basel , CH-4003 Basel, Switzerland.
  • 4 Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center , Duarte, California 91010, United States.
  • 5 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
PMID: 27933964 DOI: 10.1021/acs.jmedchem.6b01410
Abstract

The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand-androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimization of antischistosomal hydantoins.

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