Synthesis of Potent Vanin-1 Inhibitors Labelled With Carbon-14 and Deuterium.

Vanin-1 is an enzyme highly expressed in the kidneys, liver, and small intestines. Inhibition of this enzyme has been postulated as a novel approach in the treatment of several inflammatory diseases. BI 764122, BI 1585773, and BI 1595043 are very potent inhibitors of this enzyme. These three analogs share the same (S)-N-(nicotinoyl)pyrrolidin-3-yl)-N-methyl acetamide moiety. The preparation of these analogs labelled with carbon-14 was accomplished via carbon-14 carboxylation with carbon dioxide of corresponding aryl halides, followed by amide bond formation with (S)-N-(methyl)-N-(pyrrolidin-3-yl)acetamide. For metabolic considerations, the radioactive carbon was also incorporated in a cyclopropyl in [14C]-BI 764122 synthesis. The deuterium labelling of these three compounds was completed using the common moiety (S)-N-(methyl-d3)-N-(pyrrolidin-3-yl)acetamide-d3, which was prepared in three steps and then coupled to the corresponding aryl acids via amide bond.