Hip To Be Square: Oxetanes as Design Elements To Alter Metabolic Pathways
Oxetane-containing ring systems are increasingly used in medicinal chemistry programs to modulate druglike properties. We have shown previously that oxetanes are hydrolyzed to diols by human microsomal epoxide hydrolase (mEH). Mapping the enzymes that contribute to drug metabolism is important since...
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Published in | Journal of medicinal chemistry Vol. 62; no. 16; pp. 7383 - 7399 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
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American Chemical Society
22.08.2019
Amer Chemical Soc |
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Abstract | Oxetane-containing ring systems are increasingly used in medicinal chemistry programs to modulate druglike properties. We have shown previously that oxetanes are hydrolyzed to diols by human microsomal epoxide hydrolase (mEH). Mapping the enzymes that contribute to drug metabolism is important since an exaggerated dependence on one specific isoenzyme increases the risk of drug–drug interactions with co-administered drugs. Herein, we illustrate that mEH-catalyzed hydrolysis is an important metabolic pathway for a set of more structurally diverse oxetanes and the degree of hydrolysis is modulated by minor structural modifications. A homology model based on the Bombyx mori EH crystal structure was used to rationalize substrate binding. This study shows that oxetanes can be used as drug design elements for directing metabolic clearance via mEH, thus potentially decreasing the dependence on cytochromes P450. Metabolism by mEH should be assessed early in the design process to understand the complete metabolic fate of oxetane-containing compounds, and further study is required to allow accurate pharmacokinetic predictions of its substrates. |
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AbstractList | Oxetane-containing ring systems are increasingly used in medicinal chemistry programs to modulate druglike properties. We have shown previously that oxetanes are hydrolyzed to diols by human microsomal epoxide hydrolase (mEH). Mapping the enzymes that contribute to drug metabolism is important since an exaggerated dependence on one specific isoenzyme increases the risk of drug-drug interactions with co-administered drugs. Herein, we illustrate that mEH-catalyzed hydrolysis is an important metabolic pathway for a set of more structurally diverse oxetanes and the degree of hydrolysis is modulated by minor structural modifications. A homology model based on the Bombyx mori EH crystal structure was used to rationalize substrate binding. This study shows that oxetanes can be used as drug design elements for directing metabolic clearance via mEH, thus potentially decreasing the dependence on cytochromes P450. Metabolism by mEH should be assessed early in the design process to understand the complete metabolic fate of oxetane-containing compounds, and further study is required to allow accurate pharmacokinetic predictions of its substrates. Oxetane-containing ring systems are increasingly used in medicinal chemistry programs to modulate druglike properties. We have shown previously that oxetanes are hydrolyzed to diols by human microsomal epoxide hydrolase (mEH). Mapping the enzymes that contribute to drug metabolism is important since an exaggerated dependence on one specific isoenzyme increases the risk of drug-drug interactions with co-administered drugs. Herein, we illustrate that mEH-catalyzed hydrolysis is an important metabolic pathway for a set of more structurally diverse oxetanes and the degree of hydrolysis is modulated by minor structural modifications. A homology model based on the EH crystal structure was used to rationalize substrate binding. This study shows that oxetanes can be used as drug design elements for directing metabolic clearance via mEH, thus potentially decreasing the dependence on cytochromes P450. Metabolism by mEH should be assessed early in the design process to understand the complete metabolic fate of oxetane-containing compounds, and further study is required to allow accurate pharmacokinetic predictions of its substrates. |
Author | Li, Xue-Qing Weidolf, Lars Toselli, Francesca Fredenwall, Marlene Svensson, Peder Johansson, Anders Hayes, Martin A |
AuthorAffiliation | Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D AstraZeneca Integrative Research Laboratories Discovery Sciences, BioPharmaceuticals R&D |
AuthorAffiliation_xml | – name: AstraZeneca – name: Discovery Sciences, BioPharmaceuticals R&D – name: Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D – name: Integrative Research Laboratories |
Author_xml | – sequence: 1 givenname: Francesca surname: Toselli fullname: Toselli, Francesca organization: AstraZeneca – sequence: 2 givenname: Marlene surname: Fredenwall fullname: Fredenwall, Marlene organization: AstraZeneca – sequence: 3 givenname: Peder surname: Svensson fullname: Svensson, Peder organization: Integrative Research Laboratories – sequence: 4 givenname: Xue-Qing surname: Li fullname: Li, Xue-Qing organization: AstraZeneca – sequence: 5 givenname: Anders orcidid: 0000-0002-1467-6795 surname: Johansson fullname: Johansson, Anders organization: AstraZeneca – sequence: 6 givenname: Lars surname: Weidolf fullname: Weidolf, Lars organization: AstraZeneca – sequence: 7 givenname: Martin A orcidid: 0000-0002-2640-8464 surname: Hayes fullname: Hayes, Martin A email: martin.hayes@astrazeneca.com organization: AstraZeneca |
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Keywords | CYTOCHROME-P450 POTENT PHARMACOKINETICS CRYSTAL-STRUCTURE ALDEHYDE OXIDASE MICROSOMAL EPOXIDE HYDROLASE CANDIDATE INHIBITOR DISCOVERY STRATEGIES |
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Snippet | Oxetane-containing ring systems are increasingly used in medicinal chemistry programs to modulate druglike properties. We have shown previously that oxetanes... |
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SubjectTerms | Chemistry, Medicinal Life Sciences & Biomedicine Pharmacology & Pharmacy Science & Technology |
Title | Hip To Be Square: Oxetanes as Design Elements To Alter Metabolic Pathways |
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