Adamantane sulfone and sulfonamide 11-β-HSD1 Inhibitors

Sorensen, Bryan K.; Winn, Martin; Rohde, Jeff; Qi, Shuai; Wang, Jiahong; Fung, Steven; Monzon, Katina; Chiou, William J.; Stolarik, DeAnne; Imade, Hovis; Pan, Liping; Deng, X.Q.; Chovan, Linda E.; Longenecker, K.L.; Judge, Russell A.; Qin, Wenying; Brune, Michael E.; Camp, Heidi S.; Frevert, Ernst U.; Jacobson, Peer B.; Link, J. T.

doi:10.1016/j.bmcl.2006.10.008

Cited by 63 publications

(56 citation statements)

References 17 publications

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“…Fourteen of the publicly available crystal structures of human 11b-HSD1 (1XU7, [49] 1XU9, [49] 2BEL, 2ILT, [43] 2IRW, [50] 2RBE, [51] 3BYZ, [52] 3BZU, [53] 3CH6, [54] 3CZR, [55] 3D3E, [56] 3D4N, [56] 3D5Q, [57] 3EY4 [44] and 3FRJ [58] ) were superimposed to determine the shape, volume and flexibility of the substrate binding site. The NADP(H) molecules from all fourteen structures were found to be superimposable-the different inhibitors have little influence on the structure of the protein around the NADP(H).…”

Section: Molecular Modelling: Docking Studiesmentioning

confidence: 99%

“…[28,43] The replacement of the chlorinated phenyl group with a more hydrophobic adamantyl moiety was a successful attempt to produce more potent compounds. The activity of compound 13 increased by~20-fold with an IC 50 value of 302 nm, which indicated that the adamantyl group was highly favoured with such a linker system possibly due to the hydrophobic interactions in the binding region.…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

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

Pradaux-Caggiano

Thomas

et al. 2010

ChemMedChem

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11Beta-hydroxysteroid dehydrogenases (11beta-HSDs) are key enzymes regulating the pre-receptor metabolism of glucocorticoid hormones. The modulation of 11beta-HSD type 1 activity with selective inhibitors has beneficial effects on various conditions including insulin resistance, dyslipidemia and obesity. Inhibition of tissue-specific glucocorticoid action by regulating 11beta-HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases. A series of novel adamantyl ethanone compounds was identified as potent inhibitors of human 11beta-HSD1. The most active compounds identified (52, 62, 72, 92, 103 and 104) display potent inhibition of 11beta-HSD1 with IC(50) values in the 50-70 nM range. Compound 72 also proved to be metabolically stable when incubated with human liver microsomes. Furthermore, compound 72 showed very weak inhibitory activity for human cytochrome P450 enzymes and is therefore a candidate for in vivo studies. Comparison of the publicly available X-ray crystal structures of human 11beta-HSD1 led to docking studies of the potent compounds, revealing how these molecules may interact with the enzyme and cofactor.

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Section: Molecular Modelling: Docking Studiesmentioning

confidence: 99%

Section: Structure-activity Relationshipsmentioning

confidence: 99%

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

Pradaux-Caggiano

Thomas

et al. 2010

ChemMedChem

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“…Both sulfone oxygens could be hydrogen bonded to a water molecule, which itself may be involved in forming a rather long hydrogen bond to one of N123 OD1 or to one of the NADP(H) phosphate oxygens, O1A. The inhibitor in the 2IRW structure, 13 (IC 50 = 6 nM), replaces the sulfone with a carboxamide, the NH of which might form a hydrogen bond to one of the NADP(H) phosphate oxygens, O1N [36,37].…”

Section: Xu7-therementioning

confidence: 99%

“…Some of these hydrogen bonds are mutually exclusive and others are not present in every structure because the orientation of amino acid side chains or Thomas NADP(H) phosphate oxygens is incompatible with hydrogen-bond formation. The possible hydrogen bonds in the 2ILT structure are illustrated in Figure 8 [36]. In the hydrogen bonds listed in the following paragraph, the NADP(H) atoms involved in those bonds are identified by their naming in the 2ILT structure; the names of the NADP(H) oxygen atoms involved in specific bonds can change between the different structures, for example, atom O1X in one structure may be named O2X in another structure despite their being in the same or similar position.…”

Section: Cofactor Bindingmentioning

confidence: 99%

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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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11β‐Hydroxysteroid Dehydrogenase Type 1 as a Therapeutic Target for Type 2 Diabetes

Hale

Jean

2011

Metabolic Syndrome

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Adamantane sulfone and sulfonamide 11-β-HSD1 Inhibitors

Cited by 63 publications

References 17 publications

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

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

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

11β‐Hydroxysteroid Dehydrogenase Type 1 as a Therapeutic Target for Type 2 Diabetes

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