Potent and selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 labeled with carbon-13 and carbon-14.

Abstract

(S)-6-(2-Hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (1) and (4aR,9aS)-1-(1H-benzo[d]midazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1-H-indeno[2,1-b]pyridine-6-carbonitrile hydrochloride (2) are potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 enzyme. These 2 drug candidates developed for the treatment of type-2 diabetes were prepared labeled with carbon-13 and carbon-14 to enable drug metabolism, pharmacokinetics, bioanalytical, and other studies. In the carbon-13 synthesis, benzoic-13 C6 acid was converted in 7 steps and in 16% overall yield to [13 C6 ]-(1). Aniline-13 C6 was converted in 7 steps to 1H-benzimidazole-1-2,3,4,5,6-13 C6 -5-carboxylic acid and then coupled to a tricyclic chiral indenopiperidine to afford [13 C6 ]-(2) in 19% overall yield. The carbon-14 labeled (1) was prepared efficiently in 2 radioactive steps in 41% overall yield from an advanced intermediate using carbon-14 labeled methyl magnesium iodide and Suzuki-Miyaura cross coupling via in situ boronate formation. As for the synthesis of [14 C]-(2), 1H-benzimidazole-5-carboxylic-14 C acid was first prepared in 4 steps using potassium cyanide-14 C, then coupled to the chiral indenopiperidine using amide bond formation conditions in 26% overall yield.