4-Methyl-5-phenyl triazoles as selective inhibitors of 11β-hydroxysteroid dehydrogenase type I

Zhu, Yang; Olson, Steven H.; Hermanowski‐Vosatka, Anne; Mundt, Steven S.; Shah, Kashmira; Springer, Marty S.; Thieringer, Rolf; Wright, Samuel D.; Xiao, Jianying; Zokian, Hratch; Balkovec, James M.

doi:10.1016/j.bmcl.2008.04.013

Cited by 26 publications

(16 citation statements)

References 23 publications

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“…To the best of our knowledge, this is the first transition‐metal‐free synthesis of a 1‐aryl‐2‐trifluoromethyl‐1 H ‐imidazole. Previous syntheses required stoichiometric amounts of a copper salt and a CF 3 + precursor16 or used 2‐trifluoromethyl‐1 H ‐imidazole as the starting material of a copper‐catalyzed coupling reaction 17. Our procedure allows the synthesis of 1‐aryl‐2‐trifluoromethyl‐1 H ‐imidazoles from inexpensive trifluoroacetic anhydride.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of 1,2‐Diaryl‐ and 1‐Aryl‐2‐alkylimidazoles with Sterically Demanding Substituents

2013

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1,2‐Diarylimidazoles are an important class of compounds. They are frequently used as ligands for photophysically active metal complexes and also display physiological activity. We developed a new, high‐yielding procedure for the synthesis of 1,2‐diaryl‐substituted imidazoles with sterically demanding substituents at the respective ortho positions by starting from commercially available anilines and benzoic acids through the corresponding acid chlorides. The metal‐free method provides access to a variety of different substituents on the phenyl rings at N‐1 and C‐2 as well as at the 4,5‐positions of the imidazole backbone. Our new method is also suitable for the preparation of 1‐aryl‐2‐alkylimidazoles.

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Section: Resultsmentioning

confidence: 99%

Synthesis of 1,2‐Diaryl‐ and 1‐Aryl‐2‐alkylimidazoles with Sterically Demanding Substituents

2013

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“…For type 1 11β-HSD, inhibitor series include diverse scaffolds: triazoles (Merck-544) and azabicyclic sulphonamides developed by both Merck and Eli Lilly [76, 77]; pentanedioic acid diamides developed by Merck-Serono [78]; pyridinyl arylsulfonamides developed by Pfizer (PF-915275) [79]; (phenylsulfonamido-methyl)-nicotine and (phenylsulfonamido-methyl)-thiazole derivatives [80]; arylsulfonylpiperazines, piperdyl- and cyclo-benzamides developed by Amgen (Amgen 2922) [81–83]; thiazolones developed by Biovitrum (BVT-2733) [84]; 1,5-substituted-1 H -tetrazoles developed by the group at Edinburgh [85]; and adamantyl ethanones developed by Ipsen/Sterix [86]. Many of these have nM affinity for the target.…”

Section: Hsd Inhibitor Classesmentioning

confidence: 99%

Human hydroxysteroid dehydrogenases and pre-receptor regulation: Insights into inhibitor design and evaluation

Penning

2011

The Journal of Steroid Biochemistry and Molecular Biology

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Hydroxysteroid dehydrogenases (HSDs) represent a major class of NAD(P)(H) dependent steroid hormone oxidoreductases involved in the pre-receptor regulation of hormone action. This is achieved by HSDs working in pairs so that they can interconvert ketosteroids with hydroxysteroids resulting in a change in ligand potency for nuclear receptors. HSDs belong to two protein superfamilies the aldo-keto reductases and the short-chain dehydrogenase/reductases. In humans, many of the important enzymes have been thoroughly characterized including the elucidation of their three-dimensional structures. Because these enzymes play fundamental roles in steroid hormone action they can be considered to be drug targets for a variety of steroid driven diseases: e.g. metabolic syndrome and obesity, inflammation, and hormone dependent malignancies of the endometrium, prostate and breast. This article will review how fundamental knowledge of these enzymes can be exploited in the development of isoform specific HSD inhibitors from both protein superfamilies.

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“…The 4H-1,2,4-triazole core structure can be found in many potent 11b-HSD1 inhibitors reported previously. [48][49][50][51] The dramatic increase in activity could be the result of a network of interactions with the triazole ring. A docking study with compound 28 found that the highest docking score solution poses the triazole ring close to the cofactor with the triazole methyl group fitting in a pocket formed by I121, T124 and Y183.…”

Section: Compdmentioning

confidence: 99%

Discovery of Adamantyl Heterocyclic Ketones as Potent 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Vicker

Thomas

et al. 2011

ChemMedChem

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11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11β-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11β-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β-HSD1 and are selective with no activity against 11β-HSD2 and 17β-HSD1. Selected potent 11β-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.

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4-Methyl-5-phenyl triazoles as selective inhibitors of 11β-hydroxysteroid dehydrogenase type I

Cited by 26 publications

References 23 publications

Synthesis of 1,2‐Diaryl‐ and 1‐Aryl‐2‐alkylimidazoles with Sterically Demanding Substituents

Synthesis of 1,2‐Diaryl‐ and 1‐Aryl‐2‐alkylimidazoles with Sterically Demanding Substituents

Human hydroxysteroid dehydrogenases and pre-receptor regulation: Insights into inhibitor design and evaluation

Discovery of Adamantyl Heterocyclic Ketones as Potent 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitors

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