Design of A Metabolically Stable Tritium‐Tracer of the PI3Kδ‐Inhibitor CDZ173 (Leniolisib) as a Tool to Study Liver Metabolites

In this disclosure, we summarize the preliminary metabolic profiling of the PI3Kδ inhibitor CDZ173 (leniolisib, 1a) obtained from incubations of the unlabeled compound and the synthesis of its metabolically stable tritium isotopologue 1b used for metabolite structure confirmation. Access to 1b was a...

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Bibliographic Details
Published in:Helvetica chimica acta 2018-06, Vol.101 (6), p.n/a
Main Authors: Bauer, Carsten, Luu, Tong, Eggimann, Fabian, Bross, Patrick, Gertsch, Werner, Hu, Cheng, Ramstein, Philippe, Bourgailh, Julien, Glänzel, Albrecht, Dix, Ina, Guenat, Christian, Soldermann, Nicolas, Litherland, Karine, Desrayaud, Sandrine, Hengy, Jean‐Claude, Pearson, David, Blanz, Joachim, Burkhart, Christoph
Format: Article
Language:English
Subjects:
Amination
CDZ173
Conformation
conformational analysis of pyrrolidines
Hepatocytes
High-performance liquid chromatography
Inhibitors
leniolisib
Liquid chromatography
Liver
metabolism of pyrrolidines
Metabolites
NMR
Nuclear magnetic resonance
PI3Kδ inhibitor
Precursors
Pyridines
Pyrrolidine
Radioactive tracers
Spectroscopy
Stereochemistry
Tritium
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Summary:In this disclosure, we summarize the preliminary metabolic profiling of the PI3Kδ inhibitor CDZ173 (leniolisib, 1a) obtained from incubations of the unlabeled compound and the synthesis of its metabolically stable tritium isotopologue 1b used for metabolite structure confirmation. Access to 1b was achieved when a halogenated precursor was subject to Hal/3H‐exchange. Hence, [3H]CDZ173 with specific activity 630 GBq/mmol, HPLC‐RA 97% and ee = 99.2% was obtained. Synthetic key to the precursor was using a bis‐halo‐pyridine in a Pd‐catalyzed mono‐amination of the tetrahydropyrido‐pyrimidine core. Stereochemistry of the synthetic precursors were confirmed by X‐ray analysis of the unlabeled bis‐halo‐pyridines and chiral HPLC of the tritiated material. The correct position of tritium label in the target, was confirmed by 3H‐NMR difference spectroscopy. Besides, we report on the validation of the radiotracer as a tool for pre‐clinical ADME in incubations with hepatocytes. Based on this data, we present a quantitative metabolite profile of leniolisib which was confirmed by independently synthesized metabolite references. The conformation of CDZ173 was investigated by NMR suggesting two different amide backbones each with specific pyrrolidine puckerings.
ISSN:0018-019X
1522-2675
DOI:10.1002/hlca.201800044