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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.

Journal of labelled compounds & radiopharmaceuticals (2014-09-10)
Richard C Burrell, John A Easter, Michael P Cassidy, Kevin W Gillman, Richard E Olson, Samuel J Bonacorsi
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%. (13) C6 -Labeled Avagacestat was synthesized in three steps in a 15% overall yield from 4-chloro[(13) C6 ]aniline. A total of 585 mg was prepared with a ultraviolet purity of 99.9%.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cesium carbonate, ReagentPlus®, 99%
Sigma-Aldrich
Cesium carbonate, 99.9% trace metals basis
Sigma-Aldrich
Cesium carbonate, 99.95% trace metals basis
Sigma-Aldrich
Cesium carbonate, 99.995% trace metals basis
Sigma-Aldrich
Cesium carbonate, puriss. p.a., ≥99.0%
Sigma-Aldrich
Cesium carbonate, purum p.a., ≥98.0% (T)