Revisiting the SAR of the antischistosomal aryl hydantoin (Ro 13-3978)

Chunkai Wang, Qingjie Zhao, Mireille Vargas, Jeremy O. Jones, Karen White, David Shackleford, Gong Chen, Jessica Saunders, Alice Ng, Francis Chiu, Yuxiang Dong, Susan Charman, Jennifer Keiser, Jonathan L. Vennerstrom

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)10705-10718
Number of pages14
JournalJournal of Medicinal Chemistry
Volume59
Issue number23
DOIs
Publication statusPublished - 8 Dec 2016

Cite this

Wang, C., Zhao, Q., Vargas, M., Jones, J. O., White, K., Shackleford, D., ... Vennerstrom, J. L. (2016). Revisiting the SAR of the antischistosomal aryl hydantoin (Ro 13-3978). Journal of Medicinal Chemistry, 59(23), 10705-10718. https://doi.org/10.1021/acs.jmedchem.6b01410
Wang, Chunkai ; Zhao, Qingjie ; Vargas, Mireille ; Jones, Jeremy O. ; White, Karen ; Shackleford, David ; Chen, Gong ; Saunders, Jessica ; Ng, Alice ; Chiu, Francis ; Dong, Yuxiang ; Charman, Susan ; Keiser, Jennifer ; Vennerstrom, Jonathan L. / Revisiting the SAR of the antischistosomal aryl hydantoin (Ro 13-3978). In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 23. pp. 10705-10718.
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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.",
author = "Chunkai Wang and Qingjie Zhao and Mireille Vargas and Jones, {Jeremy O.} and Karen White and David Shackleford and Gong Chen and Jessica Saunders and Alice Ng and Francis Chiu and Yuxiang Dong and Susan Charman and Jennifer Keiser and Vennerstrom, {Jonathan L.}",
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Wang, C, Zhao, Q, Vargas, M, Jones, JO, White, K, Shackleford, D, Chen, G, Saunders, J, Ng, A, Chiu, F, Dong, Y, Charman, S, Keiser, J & Vennerstrom, JL 2016, 'Revisiting the SAR of the antischistosomal aryl hydantoin (Ro 13-3978)' Journal of Medicinal Chemistry, vol. 59, no. 23, pp. 10705-10718. https://doi.org/10.1021/acs.jmedchem.6b01410

Revisiting the SAR of the antischistosomal aryl hydantoin (Ro 13-3978). / Wang, Chunkai; Zhao, Qingjie; Vargas, Mireille; Jones, Jeremy O.; White, Karen; Shackleford, David; Chen, Gong; Saunders, Jessica; Ng, Alice; Chiu, Francis; Dong, Yuxiang; Charman, Susan; Keiser, Jennifer; Vennerstrom, Jonathan L.

In: Journal of Medicinal Chemistry, Vol. 59, No. 23, 08.12.2016, p. 10705-10718.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Wang, Chunkai

AU - Zhao, Qingjie

AU - Vargas, Mireille

AU - Jones, Jeremy O.

AU - White, Karen

AU - Shackleford, David

AU - Chen, Gong

AU - Saunders, Jessica

AU - Ng, Alice

AU - Chiu, Francis

AU - Dong, Yuxiang

AU - Charman, Susan

AU - Keiser, Jennifer

AU - Vennerstrom, Jonathan L.

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