Synthesis and structure–activity relationship of 2-adamantylmethyl tetrazoles as potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

2017

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-816336 as an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of carbon-14 labeled material was required for use in metabolic profiling. [Phenyl- C(U)]BMS-816336 was synthesized in 8 steps and 22% radiochemical yield from commercially available [ C(U)]bromobenzene. The radiochemical purity of [phenyl- C(U)]BMS-816336 was 100% having a specific activity of 84.4 μCi/mg or 28.8 mCi/mmol for a total of 8.9 mCi. It was also necessary to synthesize [ C ]BMS-816336 for use as a liquid chromatography/mass spectrometry standard. [ C ]BMS-816336 was also prepared in 8 labeled steps in 26% yield from [ C ]bromobenzene.

Section: Introductionmentioning

confidence: 99%

The syntheses of [¹³C₆] and [phenyl‐¹⁴C(U)]BMS‐816336, an inhibitor of 11β‐hydroxysteroid dehydrogenase type 1, for type 2 diabetes

2017

“…Excess glucocorticoids can cause increased glucose output, reduced glucose‐dependent insulin sensitivity in adipose tissue and reduced insulin secretion from the pancreas. 11β‐Hydroxysteroid dehydrogenase type 1 (11β‐HSD1) is an enzyme that catalyzes the conversion of inactive cortisone to cortisol . Transgenic mice that overexpressed 11β‐HSD1 in adipose tissue were found to exhibit metabolic disorders including obesity, insulin resistance, glucose intolerance and hyperglycemia .…”

Section: Introductionmentioning

confidence: 99%

“…11β‐Hydroxysteroid dehydrogenase type 1 (11β‐HSD1) is an enzyme that catalyzes the conversion of inactive cortisone to cortisol . Transgenic mice that overexpressed 11β‐HSD1 in adipose tissue were found to exhibit metabolic disorders including obesity, insulin resistance, glucose intolerance and hyperglycemia . 11β‐HSD1 knockout mice were found to be resistant to obesity and hyperglycemia .…”

Section: Introductionmentioning

confidence: 99%

“…Transgenic mice that overexpressed 11β‐HSD1 in adipose tissue were found to exhibit metabolic disorders including obesity, insulin resistance, glucose intolerance and hyperglycemia . 11β‐HSD1 knockout mice were found to be resistant to obesity and hyperglycemia . Therefore, it would seem that an inhibitor of 11β‐HSD1 could possibly be an efficacious therapy for the treatment of dysmetabolic syndrome and type 2 diabetes .…”

Section: Introductionmentioning

confidence: 99%

“…11β‐HSD1 knockout mice were found to be resistant to obesity and hyperglycemia . Therefore, it would seem that an inhibitor of 11β‐HSD1 could possibly be an efficacious therapy for the treatment of dysmetabolic syndrome and type 2 diabetes . BMS‐770767, as shown in Figure , represents such an 11β‐HSD1 inhibitor .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The synthesis and analysis of [phenyl‐¹⁴C(U)]BMS‐770767 and [¹³C₆]BMS‐770767 for use in discovery biotransformation, human ADME and bioanalytical studies

Bonacorsi

2016

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-770767 as an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) for type 2 diabetes was required the synthesis of carbon-14-labelled material for use in metabolic profiling and for the human adsorption, distribution, metabolism and excretion (ADME) study. Initially, [phenyl- C(U)]BMS-770767 was synthesized in two steps from a late-stage intermediate and [ C(U)]2-chlorophenol to give the desired final product in 18% yield. Later, the synthesis was completed for the human ADME clinical study using a combination of the discovery and process chemistry routes under cGMP to prepare [phenyl- C(U)]BMS-770767. The radiochemical purity of the synthesized [phenyl- C(U)]BMS-770767 after dilution with unlabelled clinical grade BMS-770767 was 99.1% having a specific activity of 1.61 μCi/mg. In addition, to support the quantification of BMS-770767 in LC/MS analyses, [ C ]BMT-770767 was prepared in two steps from a late-stage intermediate and [ C ]2-chlorophenol.

The syntheses of [¹⁴C]BMS‐823778 for use in a human ADME clinical study and of [¹³CD₃¹³CD₂]BMT‐094817, a stable‐isotope labeled standard of a newly detected human metabolite

Tran

Lago

et al. 2016

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-823778 as an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of carbon-14-labeled material was required for use in a human adsorption, distribution, metabolism, and excretion (ADME) study. The HCl salt form of [(14) C]BMS-823778 was synthesized in two steps from commercially available [2-(14) C]acetone. The radiochemical purity of the synthesized [(14) C]BMS-823778 after dilution with unlabeled clinical-grade BMS-823778 was 99.5% having a specific activity of 7.379 μCi/mg. One result of the human ADME study was the detection of a new human metabolite, BMT-094817. To support the quantification of BMT-094817 in clinical samples, it was necessary to synthesize [(13) CD3 (13) CD2 ]BMT-094817 for use as a liquid chromatography/mass spectrometry standard. [(13) CD3 (13) CD2 ]BMT-094817 was prepared in five labeled steps from [(13) CD3 ]iodomethane.