Stable isotope synthesis of glycine transporter 1 inhibitor Iclepertin (BI 425809) and its major metabolites

Iclepertin (BI 425809) is a potent and selective GlyT-1 inhibitor being developed for the treatment of schizophrenia. The detailed stable isotope synthesis of this drug candidate and its major metabolites is described. Stable isotope labeledIclepertin (BI 425809, 1) and its major metabolites are needed as internal standards in bioanalytical studies.BI 425809 consists of two main building blocks, 5-methylsulfonyl-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]benzoic acid (2) and 3-[(1R,5R)-3-azabicyclo[3.1.0]hexan-5-yl]-5-(trifluoromethyl)isoxazole (3) linked to each other via an amide bond. We used fluoro[13C6]benzene as the starting material in the preparation of[13C6]-2. This intermediate was then employed to access carbon 13 labeledIclepertin ([13C6]-1) and other metabolites. The major metaboliteBI 761036 (6), which resulted from cytochrome P450 oxidation and amide hydrolysis ofBI 425809, was prepared labeled with carbon 13 and nitrogen 15 via two synthetic routes. In the first route, diethyl [13C3]malonate, [13C]methyl iodide, and hydroxyl[15N]amine were used to provide[13C4,15N]-BI 761036 ([13C4,15N]-6a) in 13 steps in 6% overall yield, whereas in the second route, [13C3]propargyl alcohol, potassium [13C]cyanide, and [15N]ammonia were used to furnish[13C4,15N]-BI 761036 ([13C4,15N]-6b) in 11 steps in 1% overall yield. The detailed stable isotope synthesis of1 and its major metabolites is described.

Source: Journal of Labelled Compounds and Radiopharmaceuticals - September 21, 2023 Category: Biochemistry Authors: Bachir Latli, Matt J. Hrapchak, Maxim Chevliakov, Lalith P. Samankumara, Rogelio P. Frutos, Heewon Lee Tags: RESEARCH ARTICLE Source Type: research