Synthesis of a dual carbon-14-labeled calcitonin gene-related peptide receptor antagonist for use in a human absorption-distribution-metabolism-elimination study.

Oral calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be effective in the acute and preventive treatment of migraine. CGRP receptor antagonists offer safety advantages over triptans because they are not active vasoconstrictors, which reduces cardiovascular risks. Bristol Myers Squibb discovered a high affinity CGRP receptor antagonist BMS-927711 for the treatment of migraine now FDA approved as Nurtec® ODT (rimegepant). Dual-labeled [14 C]-BMS-927711 was prepared and used in a human absorption-distribution-metabolism-elimination (ADME) study. A dual-labeled analog of BMS-927711 was required to fully track the compound's metabolic transformation. The carbon-14-labeled synthesis of both right side and left side portions of [14 C]-BMS-927711 is described.

Synthesis of tritium labeled 30-KDa PEG and conjugation to form [3 H]Pegbelfermin.

Non-alcoholic steatohepatitis (NASH) is the most chronic liver condition in the western population and is fueled by the obesity and type 2 diabetes epidemic. Pegbelfermin (1), a PEGylated human fibroblast growth factor 21 (FGF21) analogue, has previously been shown to improve markers of metabolism and liver fibrosis in obese patients with type 2 diabetes. Radiolabeled Pegbelfermin was needed to access the accumulation of intact drug and metabolized PEG. In an effort to accomplish both goals with one labeled synthesis, the isotopic label was positioned in the PEG. A total of 21 mCi of tritium labeled Pegbelfermin was synthesized having a specific activity of 21.6 Ci/mmol for use in animal studies.

Synthesis of isotopically labeled daclatasvir for use in human clinical studies.

Daclatasvir is a novel hepatitis C virus NS5A inhibitor developed by Bristol-Myers Squibb and marketed as Daklinza®. The need to support the development of daclatasvir required the synthesis of carbon-14 labeled material for use in human absorption, distribution, metabolism, and excretion studies. A total of 7.53 mCi of [(14) C]-daclatasvir was synthesized in eight steps from commercially available [(14) C]-copper cyanide. The radiochemical purity was 99.6%, and specific activity was 3.86 µCi/mg. To support a human absolute bioavailability study, 5.56 g of [(13) C2 , (15) N4 ]-daclatasvir was synthesized in four steps.

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

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%.

An alternative and robust synthesis of [(13) C4 ]Baraclude® (entecavir).

Stable isotope-labeled [(13) C4 ]entecavir (1) was prepared in 11 steps. Commercially available [(13) C]guanidine hydrochloride and diethyl[1,2,3-(13) C3 ]malonate were condensed to yield 2-amino[2,4,5,6-(13) C4 ]pyrimidine-4,6-diol (8). This was converted to the desired purine (7) in five steps. Introduction of the chiral epoxide was followed by subsequent deprotection to give [(13) C4 ]entecavir (1), in an overall yield of 5.7% from labeled precursors. The chemical purity of the title compound was determined to be >99% by HPLC. The isotopic distribution was determined by mass spectrometry to be 282[M + 4], 98.4%; 281[M + 3], 1.6%; and 278[M + 0], <0.1%.