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

[Image: see text] 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 antia...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2016
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5150661/
https://www.ncbi.nlm.nih.gov/pubmed/27933964
http://dx.doi.org/10.1021/acs.jmedchem.6b01410
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author 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.
author_facet 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.
author_sort Wang, Chunkai
collection PubMed
description [Image: see text] 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.
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spelling pubmed-51506612016-12-14 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. J Med Chem [Image: see text] 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. American Chemical Society 2016-11-15 2016-12-08 /pmc/articles/PMC5150661/ /pubmed/27933964 http://dx.doi.org/10.1021/acs.jmedchem.6b01410 Text en Copyright © 2016 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle 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)
title Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978)
title_full Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978)
title_fullStr Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978)
title_full_unstemmed Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978)
title_short Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978)
title_sort revisiting the sar of the antischistosomal aryl hydantoin (ro 13-3978)
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5150661/
https://www.ncbi.nlm.nih.gov/pubmed/27933964
http://dx.doi.org/10.1021/acs.jmedchem.6b01410
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