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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
Author(s) -
Burrell Richard C.,
Easter John A.,
Cassidy Michael P.,
Gillman Kevin W.,
Olson Richard E.,
Bonacorsi Samuel J.
Publication year - 2014
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.3224
Subject(s) - chemistry , radiosynthesis , yield (engineering) , specific activity , carbon 14 , isotopes of carbon , radiochemistry , pharmacology , drug , bioanalysis , combinatorial chemistry , nuclear chemistry , in vivo , biochemistry , chromatography , organic chemistry , enzyme , medicine , materials science , physics , quantum mechanics , total organic carbon , metallurgy , microbiology and biotechnology , biology
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 C 6 ‐Labeled Avagacestat was synthesized in three steps in a 15% overall yield from 4‐chloro[ 13 C 6 ]aniline. A total of 585 mg was prepared with a ultraviolet purity of 99.9%.