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

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• 作者：Chunkai Wang ; Qingjie Zhao ; Mireille Vargas ; Jeremy O. Jones ; Karen L. White ; David M. Shackleford ; Gong Chen ; Jessica Saunders ; Alice C. F. Ng ; Francis C. K. Chiu ; Yuxiang Dong ; Susan A. Charman ; Jennifer Keiser ; Jonathan L. Vennerstrom
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：59
• 期：23
• 页码：10705-10718
• 全文大小：608K
• ISSN：1520-4804

文摘

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 LogD_7.4, 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.