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

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 (US)
Pages (from-to)10705-10718
Number of pages14
JournalJournal of Medicinal Chemistry
Volume59
Issue number23
DOIs
StatePublished - Dec 8 2016

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Hydantoins
Androgen Receptors
Protein Binding
Solubility
Blood Proteins
Ligands
Ro 13-3978
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Wang, C., Zhao, Q., Vargas, M., Jones, J. O., White, K. L., Shackleford, D. M., ... 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

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

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

Research output: Contribution to journalArticle

Wang, C, Zhao, Q, Vargas, M, Jones, JO, White, KL, Shackleford, DM, Chen, G, Saunders, J, Ng, ACF, Chiu, FCK, Dong, Y, Charman, SA, 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
Wang C, Zhao Q, Vargas M, Jones JO, White KL, Shackleford DM et al. Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978). Journal of Medicinal Chemistry. 2016 Dec 8;59(23):10705-10718. https://doi.org/10.1021/acs.jmedchem.6b01410
Wang, Chunkai ; Zhao, Qingjie ; Vargas, Mireille ; Jones, Jeremy O. ; White, Karen L. ; Shackleford, David M. ; Chen, Gong ; Saunders, Jessica ; Ng, Alice C.F. ; Chiu, Francis C.K. ; Dong, Yuxiang ; Charman, Susan A. ; 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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