Premium
Design and synthesis of deuterated boceprevir analogs with enhanced pharmacokinetic properties
Author(s) -
Morgan Adam J.,
Nguyen Sophia,
Uttamsingh Vinita,
Bridson Gary,
Harbeson Scott,
Tung Roger,
Masse Craig E.
Publication year - 2011
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.1905
Subject(s) - boceprevir , chemistry , in vitro , deuterium , combinatorial chemistry , biochemistry , stereochemistry , physics , quantum mechanics , ribavirin , genotype , gene
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 devised synthetic routes allowed for site‐selective deuterium incorporation with high levels of isotopic purity. Application of the DCE Platform™ to boceprevir enabled the identification of several deuterated analogs that display marked levels of in vitro metabolic stabilization. Most notably, analog 1g exhibits a near doubling of in vitro half‐life in human liver microsomal assays. The details of the convergent synthetic route to the boceprevir isotopologs and the results of the metabolic stability assays are described herein.