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 (&l...
محفوظ في:
| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , , , , , , , , , , , |
| منشور في: |
2025
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إضافة وسم
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| الملخص: | 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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