Synthesis of carbon‐14 and stable isotope labeled Avagacestat: a novel gamma secretase inhibitor for the treatment of Alzheimer's disease. (5th September 2014)

• Record Type: Journal Article
• Authors: Burrell, Richard C.; Easter, John A.; Cassidy, Michael P.; Gillman, Kevin W.; Olson, Richard E.; Bonacorsi, Samuel J.
• Is Part Of: Journal of labelled compounds & radiopharmaceuticals. Volume 57:Number 10(2014)
• Page Start: 600
• Page End: 605
• Publication Date: 2014-09-05
• Subjects: Tracers (Chemistry) -- Periodicals; Radiopharmaceuticals -- Periodicals; 615.8424
• DOI: 10.1002/jlcr.3224
• Languages: English
• ISSNs: 0362-4803

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Bristol‐Myers Squibb and others are developing drugs that target novel mechanisms to combat Alzheimer's disease. <italic>γ</italic>‐Secretase inhibitors are one class of potential therapies that have received considerable attention. (<italic>R</italic>)‐2‐(4‐Chloro‐<italic>N</italic>‐(2‐fluoro‐4‐(1, 2, 4‐oxadiazol‐3‐yl)benzyl)phenylsulfonamido)‐5, 5, 5‐trifluoropentanamide (Avagacestat) is a <italic>γ</italic>‐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.</p> <p>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%.</p> </abstract>