Characterization of Divergent Metabolic Pathways in Elucidating an Unexpected, Slow-Forming, and Long Half-Life Major Metabolite of Iclepertin

Chan, Tom S.; Byer-Alcorace, Alexander J.; Latli, Bachir; Liu, Pingrong; Maw, Hlaing; Raymond, Klairynne G.; Scaringella, Young-Sun; Teitelbaum, Aaron M.; Wang, Ting; Whitcher-Johnstone, Andrea; Taub, Mitchell E.

doi:10.1007/s11095-023-03530-z

Cited by 3 publications

(1 citation statement)

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“…This compound consists of 5‐methylsulfonyl‐2‐[(1 R )‐2,2,2‐trifluoro‐1‐methyl‐ethoxy]benzoic acid ( 2 ) linked via an amide bond to 3‐[(1 R ,5 R )‐3‐azabicyclo[3.1.0]hexan‐5‐yl]‐5‐(trifluoromethyl)isoxazole ( 3 ) (Figure 1). Iclepertin is metabolized in male human plasma, urine, and feces to at least 20 metabolites 2 . The structures of 11 of these metabolites were unequivocally determined.…”

Section: Introductionmentioning

confidence: 99%

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

Latli,

Hrapchak,

Chevliakov

et al. 2023

Labelled Comp Radiopharmac

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Stable isotope labeled Iclepertin (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 labeled Iclepertin ([13C6]‐1) and other metabolites. The major metabolite BI 761036 (6), which resulted from cytochrome P450 oxidation and amide hydrolysis of BI 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 of 1 and its major metabolites is described.

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Section: Introductionmentioning

confidence: 99%