Discovery of Adamantyl Ethanone Derivatives as Potent 11β‐Hydroxysteroid Dehydrogenase Type 1 (11β‐HSD1) Inhibitors

Su, Xiaoyan; Pradaux-Caggiano, Fabienne; Thomas, Mark; Szeto, Michelle W. Y.; Halem, Heather; Culler, Michael D.; Vicker, Nigel; Potter, Barry V. L.

doi:10.1002/cmdc.201000081

Cited by 14 publications

(24 citation statements)

References 58 publications

(66 reference statements)

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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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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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“…Compound 7 (Sterix) inhibits human 11β-HSD1 with IC 50 = 56 nM [32]. In metabolism studies with human liver microsomes it was found to be stable (87% remaining after 30 min) with a half-life of 59 min, a clearance rate of 11 μl/min/mg and no detectable metabolites.…”

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confidence: 99%

Crystal Structures of 11β-Hydroxysteroid Dehydrogenase Type 1 and Their Use in Drug Discovery

Thomas

Potter

2011

Future Med. Chem.

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Cortisol is synthesized by 11β-hydroxysteroid dehydrogenase type 1, inhibitors of which may treat disease associated with excessive cortisol levels. The crystal structures of 11β-hydroxysteroid dehydrogenase type 1 that have been released may aid drug discovery. The crystal structures have been analyzed in terms of the interactions between the protein and the ligands. Despite a variety of structurally different inhibitors the crystal structures of the proteins are quite similar. However, the differences are significant for drug discovery. The crystal structures can be of use in drug discovery, but care needs to be taken when selecting structures for use in virtual screening and ligand docking.A significant problem facing society is the increase in obesity. Often observed in obese people is metabolic syndrome, a disease characterized by a variety of symptoms including congestive heart failure, hypertension, atherogenic lipidemia, glucose intolerance, insulin resistance and Type II diabetes [1]. These symptoms, widely recognized as being risk factors for cardio vascular disease [2], are also associated with high levels of the glucocorticoid hormone cortisol [3,4]. Glucocorticoid hormones play essential roles in a range of physiological processes including the regulation of carbohydrate, lipid and bone metabolism, maturation and differentiation of cells, and modulation of inflammatory responses and stress [5][6][7]. They exert their effect primarily through binding to glucocorticoid receptors, leading to altered target gene transcription. Symptoms similar to those of metabolic syndrome are observed in patients suffering from Cushing's syndrome, which is marked by increased glucocorticoid levels [8]. The similarity of these symptoms suggests that the suppression of glucocorticoid activity may be a treatment for the individual indications of metabolic syndrome [9] despite the fact that in metabolic syndrome circulating glucocorticoid levels are not usually elevated [10]. Therefore, it is speculated that intercellular, but particularly intracellular local levels of glucocorticoid regulated by

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“…1-(2,3-Dihydrobenzo[b] [1,4]dioxin-6-yl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)sulfinyl)ethanone (19). An off-white semi-solid (24 mg, 18% yield) was obtained.…”

Section: General Procedures A: Synthesis Of Aryl Ethanone Sulphanyl Dementioning

confidence: 99%

“…[19][20][21] We previously reported that compounds 1 and 2 ( Fig. 1) are highly active 11b-HSD1 inhibitors when tested on an HEK293 cell line transfected with the human 11b-HSD1 gene.…”

Section: Introductionmentioning

confidence: 95%

Synthesis and evaluation of thiadiazole derivatives as inhibitors of 11β-hydroxysteroid dehydrogenase type 1

Pradaux-Caggiano

Vicker

et al. 2012

Med. Chem. Commun.

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Regulation of tissue-specific glucocorticoid action by inhibiting 11b-HSD1 activity is regarded as a potential viable treatment for metabolic and cardiovascular diseases. Our effort to find an alternative to the highly favoured adamantyl moiety found in many potent 11b-HSD1 inhibitors led to the synthesis and SAR study of a series of phenyl ethanone thiadiazole derivatives. Potent compounds were identified with IC 50 values in the range 100-300 nM in biological evaluation on an HEK293 cell line stably transfected with the human HSD11B1 gene. These compounds are selective with no activity against human 11b-HSD2. An SAR study revealed the favoured combination of phenyl substitution and the linker system being meta-methoxy with a sulphide linker (18) or a para-trifluoromethyl with sulphoxide linker (27). Docking of 3 into a crystal structure of the enzyme shows how the substituted phenyl group of this new series might mimic the adamantane motif. Potent inhibitors 18 and 27 are new templates for further optimization.

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Discovery of Adamantyl Ethanone Derivatives as Potent 11β‐Hydroxysteroid Dehydrogenase Type 1 (11β‐HSD1) Inhibitors

Cited by 14 publications

References 58 publications

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

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

Crystal Structures of 11β-Hydroxysteroid Dehydrogenase Type 1 and Their Use in Drug Discovery

Synthesis and evaluation of thiadiazole derivatives as inhibitors of 11β-hydroxysteroid dehydrogenase type 1

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