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Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability

Fostemsavir/temsavir is an investigational HIV-1 entry inhibitor currently in late-stage clinical trials. Although it holds promise to be a first-in-class Env-targeted entry inhibitor for the clinic, issues with bioavailability relegate its use to salvage therapies only. As such, the development of...

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Detalles Bibliográficos
Autores principales: Karadsheh, Rama, Meuser, Megan E., Cocklin, Simon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144373/
https://www.ncbi.nlm.nih.gov/pubmed/32245167
http://dx.doi.org/10.3390/molecules25061430
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author Karadsheh, Rama
Meuser, Megan E.
Cocklin, Simon
author_facet Karadsheh, Rama
Meuser, Megan E.
Cocklin, Simon
author_sort Karadsheh, Rama
collection PubMed
description Fostemsavir/temsavir is an investigational HIV-1 entry inhibitor currently in late-stage clinical trials. Although it holds promise to be a first-in-class Env-targeted entry inhibitor for the clinic, issues with bioavailability relegate its use to salvage therapies only. As such, the development of a small molecule HIV-1 entry inhibitor that can be used in standard combination antiretroviral therapy (cART) remains a longstanding goal for the field. We previously demonstrated the ability of extending the chemotypes available to this class of inhibitor as the first step towards this overarching goal. In addition to poor solubility, metabolic stability is a crucial determinant of bioavailability. Therefore, in this short communication, we assess the metabolic stabilities of five of our novel chemotype entry inhibitors. We found that changing the piperazine core region of temsavir alters the stability of the compound in human liver microsome assays. Moreover, we identified an entry inhibitor with more than twice the metabolic stability of temsavir and demonstrated that the orientation of the core replacement is critical for this increase. This work further demonstrates the feasibility of our long-term goal—to design an entry inhibitor with improved drug-like qualities—and warrants expanded studies to achieve this.
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spelling pubmed-71443732020-04-13 Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability Karadsheh, Rama Meuser, Megan E. Cocklin, Simon Molecules Communication Fostemsavir/temsavir is an investigational HIV-1 entry inhibitor currently in late-stage clinical trials. Although it holds promise to be a first-in-class Env-targeted entry inhibitor for the clinic, issues with bioavailability relegate its use to salvage therapies only. As such, the development of a small molecule HIV-1 entry inhibitor that can be used in standard combination antiretroviral therapy (cART) remains a longstanding goal for the field. We previously demonstrated the ability of extending the chemotypes available to this class of inhibitor as the first step towards this overarching goal. In addition to poor solubility, metabolic stability is a crucial determinant of bioavailability. Therefore, in this short communication, we assess the metabolic stabilities of five of our novel chemotype entry inhibitors. We found that changing the piperazine core region of temsavir alters the stability of the compound in human liver microsome assays. Moreover, we identified an entry inhibitor with more than twice the metabolic stability of temsavir and demonstrated that the orientation of the core replacement is critical for this increase. This work further demonstrates the feasibility of our long-term goal—to design an entry inhibitor with improved drug-like qualities—and warrants expanded studies to achieve this. MDPI 2020-03-21 /pmc/articles/PMC7144373/ /pubmed/32245167 http://dx.doi.org/10.3390/molecules25061430 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Karadsheh, Rama
Meuser, Megan E.
Cocklin, Simon
Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability
title Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability
title_full Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability
title_fullStr Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability
title_full_unstemmed Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability
title_short Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability
title_sort composition and orientation of the core region of novel hiv-1 entry inhibitors influences metabolic stability
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144373/
https://www.ncbi.nlm.nih.gov/pubmed/32245167
http://dx.doi.org/10.3390/molecules25061430
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