title: Synthesis of carbon-14 and stable isotope labeled Avagacestat: a novel gamma secretase inhibitor for the treatment of Alzheimer's disease.
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%.
authors.affiliation: Discovery Chemistry Platforms, Radiochemistry, Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT, 06492, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Burrell
authors.forename: John A
authors.initials: JA
authors.lastname: Easter
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cassidy
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Gillman
authors.forename: Richard E
authors.initials: RE
authors.lastname: Olson
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Bonacorsi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D002250:Carbon Radioisotopes / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D010069:Oxadiazoles / Q000138:chemical synthesis*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D013449:Sulfonamides / Q000138:chemical synthesis*
chemical_list: C554092:BMS 708163; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; carbon-14 labeling; stable isotope labeling; γ-secretase inhibitors