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Synthesis of carbon-14 and stable isotope labeled Avagacestat: a novel gamma secretase inhibitor for the treatment of Alzheimer's disease.

Authors :
Burrell, Richard C.
Easter, John A.
Cassidy, Michael P.
Gillman, Kevin W.
Olson, Richard E.
Bonacorsi, Samuel J.
Source :
Journal of Labelled Compounds & Radiopharmaceuticals. Aug2014, Vol. 57 Issue 10, p600-605. 6p.
Publication Year :
2014

Abstract

Bristol-Myers Squibb and others are developing drugs that target novel mechanisms to combat Alzheimer's disease. γ-Secretase inhibitors are one class of potential therapies that have received considerable attention. ( R)-2-(4-Chloro- N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide (Avagacestat) is a γ-secretase-inhibiting drug that has been investigated by Bristol-Myers Squibb in preclinical and clinical studies. An important step in the development process was the synthesis of a carbon-14-labeled analog for use in a human absorption, distribution, metabolism, and excretion study and a stable isotope labeled analog for use as a standard in bioanalytical assays to accurately quantify the concentration of the drug in biological samples. Carbon-14 labeled Avagacestat was synthesized in seven steps in a 33% overall yield from carbon-14 labeled potassium cyanide. A total of 5.95 mCi was prepared with a specific activity of 0.81 μCi/mg and a radiochemical purity of 99.9%. 13C6-Labeled Avagacestat was synthesized in three steps in a 15% overall yield from 4-chloro[13C6]aniline. A total of 585 mg was prepared with a ultraviolet purity of 99.9%. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
03624803
Volume :
57
Issue :
10
Database :
Academic Search Index
Journal :
Journal of Labelled Compounds & Radiopharmaceuticals
Publication Type :
Academic Journal
Accession number :
98488304
Full Text :
https://doi.org/10.1002/jlcr.3224