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- C acid was converted in 7 steps and in 16% overall yield to [ C ]-(1). Aniline- C was converted in 7 steps to 1H-benzimidazole-1-2,3,4,5,6- C -5-carboxylic acid and then coupled to a tricyclic chiral indenopiperidine to afford [ C ]-(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 [ C]-(2), 1H-benzimidazole-5-carboxylic- C acid was first prepared in 4 steps using potassium cyanide- C, then coupled to the chiral indenopiperidine using amide bond formation conditions in 26% overall yield.

N-Methylation of BI 187004 by Thiol S-Methyltransferase

“…HPLC-grade solvents [acetonitrile, methanol, water, and dimethylsulfoxide (DMSO)] were purchased from Sigma-Aldrich. BI 187004 (Wei et al, 2016), 13 C 6 -BI 187004 (Latli et al, 2017), M1, and N-methylbenzimidazole regioisomer 2 (M14) were synthesized internally at Boehringer Ingelheim Pharmaceuticals, Inc. (Ridgefield, CT).…”

Synthesis of Oxazinanones: Intramolecular Cyclization of Amino Acid-Derived Diazoketones via Silica-Supported HClO4 Catalysis

“…Some important examples are the anti-HIV drug Efavirenz (Staszewski et al, 1999) and the potent anticancer agent Maytansine (Rao et al, 1979) and its synthetic derivatives Maytansinoid (Blanc et al, 2011) and Ansamitocin P3 (Taft et al, 2012). Other significant biological activities described for this class of compounds are: antibacterial (Zanatta et al, 2006; Wang, 2008), anti-influenza (Kuznetsov et al, 2017), anti-inflammatory (Ullrich et al, 2004), antidiabetes [11β HSD1 inhibitor (BI 135585)] (Zhuang et al, 2017), antithrombotic (Jin and Confalone, 2000), antialzheimer (Fuchs et al, 2007), and enzyme inhibiting [(Latli et al, 2017); Figure 1]. Furthermore, they are extensively used as valuable synthetic intermediates in fine chemicals (Woodward et al, 1981; Wang et al, 1982; Hilborn et al, 2001; Takahata et al, 2002; Wang and Tunge, 2006), cosmetics (Zofchak, 2003), and pesticides (Hino et al, 2008).…”

Corrigendum: Potent and selective inhibitors of 11β‐hydroxysteroid dehydrogenase type 1 labeled with carbon‐13 and carbon‐14

“…Subsequent to the publication of this article, this corrigendum corrects the following: The author name to Yongda Zhang. Surname of the first author in reference 17 has been corrected to Zhang. …”