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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2016
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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. |
format | Online Article Text |
id | pubmed-5150661 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
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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