Structure–Activity Relationship of Antischistosomal Aryl Hydantoin (AR102)

As exemplified by Ro 13-3978 (<b>1</b>), aryl hydantoins were identified in the early 1980s as a promising antischistosomal chemotype. We now describe the structure-activity relationship (SAR) of this compound series, which led to the discovery of the drug development candidate AR102 (<b>5</b>). These aryl hydantoins had good in vitro ADME profiles, with calculated polar surface area (PSA) values of 49-87 Å, measured LogD<sub>7.4</sub> values of 1.2-3.5, and aqueous kinetic solubilities of 25 to >100 μg/mL. The two key advances in our optimization of <b>1</b> were replacing the hydrogen atoms of the <i>gem</i>-dimethyl substructure with deuterium or fluorine atoms to slow Phase I metabolism and swapping the aryl trifluoromethyl substituent with difluoroethyl or difluoropropyl substituents to abolish antiandrogenic effects. There was no direct correlation between <i>C</i><sub>max</sub> or AUC<sub>0-last</sub> values and antischistosomal activity; however, with only one exception, compounds with the highest antischistosomal activities also had the highest exposures.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-10-14
DOI
https://doi.org/10.1021/acs.jmedchem.5c02056
Primary Topic
Parasites and Host Interactions
Type
article
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article

Structure–Activity Relationship of Antischistosomal Aryl Hydantoin (AR102)

Deepender Kaushik, Jeremy O. Jones, Jonathan L. Vennerstrom, Michael J. Campbell et al.
Journal of Medicinal Chemistry
Parasites and Host Interactions
article

Structure–Activity Relationship of Antischistosomal Aryl Hydantoin (AR102)

Deepender Kaushik, Jeremy O. Jones, Jonathan L. Vennerstrom, Michael J. Campbell, Cécile Häberli, Derek A. Leas, David M. Shackleford, Yuxiang Dong, Alexander I. Wallick, Karen L. White, Paul H. Davis, Susan A. Charman, Jianbo Wu, Jennifer Keiser
article en

Abstract

As exemplified by Ro 13-3978 (<b>1</b>), aryl hydantoins were identified in the early 1980s as a promising antischistosomal chemotype. We now describe the structure-activity relationship (SAR) of this compound series, which led to the discovery of the drug development candidate AR102 (<b>5</b>). These aryl hydantoins had good in vitro ADME profiles, with calculated polar surface area (PSA) values of 49-87 Å, measured LogD<sub>7.4</sub> values of 1.2-3.5, and aqueous kinetic solubilities of 25 to >100 μg/mL. The two key advances in our optimization of <b>1</b> were replacing the hydrogen atoms of the <i>gem</i>-dimethyl substructure with deuterium or fluorine atoms to slow Phase I metabolism and swapping the aryl trifluoromethyl substituent with difluoroethyl or difluoropropyl substituents to abolish antiandrogenic effects. There was no direct correlation between <i>C</i><sub>max</sub> or AUC<sub>0-last</sub> values and antischistosomal activity; however, with only one exception, compounds with the highest antischistosomal activities also had the highest exposures.

Journal of Medicinal ChemistryVol. 68(20)
University of Nebraska at Omaha (US), City Of Hope National Medical Center (US), Nebraska Medical Center (US), Swiss Tropical and Public Health Institute (CH), University of Basel (CH), Beckman Research Institute, Monash University (AU), University of Nebraska Medical Center (US)
Openalex Percentile: Top 70%
Parasites and Host Interactions
DOIOpen Access PDFOpenAlex
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