Design and synthesis of deuterated boceprevir analogs with enhanced pharmacokinetic properties
| Autor: | Craig E. Masse, Adam J. Morgan, Gary W. Bridson, Vinita Uttamsingh, Roger D. Tung, Sophia Nguyen, Scott L. Harbeson |
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| Rok vydání: | 2011 |
| Předmět: |
Human liver
Stereochemistry Hepatitis C virus Organic Chemistry medicine.disease_cause Biochemistry In vitro Analytical Chemistry chemistry.chemical_compound chemistry Pharmacokinetics Deuterium Boceprevir Drug Discovery Hcv ns3 protease medicine Radiology Nuclear Medicine and imaging Protease inhibitor (pharmacology) Spectroscopy |
| Zdroj: | Journal of Labelled Compounds and Radiopharmaceuticals. 54:613-624 |
| ISSN: | 0362-4803 |
| DOI: | 10.1002/jlcr.1905 |
| Popis: | As part of an ongoing effort to apply the Deuterated Chemical Entity Platform (DCE Platform™) to clinically validated drugs,the synthesis of deuterated analogs of the hepatitis C virus protease inhibitor boceprevir was carried out. The devisedsynthetic routes allowed for site‐selective deuterium incorporation with high levels of isotopic purity. Application of theDCE Platform™ to boceprevir enabled the identification of several deuterated analogs that display marked levels of in vitrometabolic stabilization. Most notably, analog 1g exhibits a near doubling of in vitro half‐life in human liver microsomalassays. The details of the convergent synthetic route to the boceprevir isotopologs and the results of the metabolic stabilityassays are described herein. Copyright © 2011 John Wiley & Sons, Ltd.Keywords: deuteration; DCE Platform; boceprevir; HCV NS3 protease; KIE |
| Databáze: | OpenAIRE |
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