Discovery of Novel, Potent Benzamide Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Exhibiting Oral Activity in an Enzyme Inhibition ex Vivo Model<sup>▽</sup>

Julian, Lisa D.; Wang, Zhong Lin; Bostick, Tracy; Caille, Seb; Choi, Rebekah; DeGraffenreid, Michael; Di, Yongmei; He, Xiao; Hungate, Randall W.; Jaén, Juan C.; Liu, Jinsong; Monshouwer, Mario; McMinn, Dustin L.; Rew, Yosup; Sudom, Athena; Sun, Daqing; Tu, Hua; Ursu, Stefania; Walker, Nigel; Yan, Xuelei; Ye, Qiuping; Powers, Jay P.

doi:10.1021/jm800310g

Cited by 40 publications

(21 citation statements)

References 14 publications

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“…M179 in 3D4N_b and 3D4N_d has alternate side chain conformations but both make contact with the cyclopropyl group. The water-mediated hydrogen bond to the NADP(H) does not exist in the 3D4N_d structure as the water is missing [43,44].…”

Section: Rbe 3byz 3bzu and 3ey4-mentioning

confidence: 99%

“…The cyclohexyl ring is positioned slightly differently to the piperidine ring but makes the same interactions. The 3-pyridyl ring makes substantial contacts with P178 and M179, and lesser contacts with L126, Y177 and V227 [43].…”

Section: Hfg and 3h6k-3hfgmentioning

confidence: 99%

“…Details of eighteen crystal structures of human 11β-HSD1 (Table 1) have been released [35][36][37][38][39][40][41][42][43][44][45][46][47][48]; these have a variety of inhibitors bound (9-26; Figure 3). In rodents, 11β-HSD1 catalyzes the reduction of 11-dehydrocorticosterone (1b) to corticosterone (2b; Figure 1).…”

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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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Section: Rbe 3byz 3bzu and 3ey4-mentioning

confidence: 99%

Section: Hfg and 3h6k-3hfgmentioning

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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“…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%

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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“…Several and distinct selective 11 -HSD1 inhibitors are being produced, developed and tested in vitro, ex vivo and in vivo, in normal animals, rodent models of metabolic alterations or disease (hyperglycemia, dyslipidemia, atherosclerosis, IR, T2DM, obesity, diet-induced obesity and/or MetSyn) and some of them already in humans, healthy or not (Alberts et al, 2002;Alberts et al, 2003;Barf et al, 2002;Bhat et al, 2008;Bujalska et al, 2008a;Cho et al, 2009;Cooper & Stewart, 2009;Coppola et al, 2005;Courtney et al, 2008;Feig et al, 2011;Gathercole & Stewart, 2010;Ge et al, 2010;Hermanowski-Vosatka et al, 2005;Hollis & Huber, 2011;Hughes et al, 2008;Hult et al, 2006;Johansson et al, 2008;Julian et al, 2008;J. Liu et al, 2011;Morgan et al, 2009;Morgan & Tomlinson, 2010;Morton, 2010;Park et al, 2011;Rosenstock et al, 2010;U.…”

Section: β-Hsd1 Inhibition Studiesmentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenase Type 1 and the Metabolic Syndrome

Pereira¹,

Martins²,

Azevedo³

et al. 2011

Steroids - Clinical Aspect

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Discovery of Novel, Potent Benzamide Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Exhibiting Oral Activity in an Enzyme Inhibition ex Vivo Model^▽

Cited by 40 publications

References 14 publications

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

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

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

11β-Hydroxysteroid Dehydrogenase Type 1 and the Metabolic Syndrome

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Discovery of Novel, Potent Benzamide Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Exhibiting Oral Activity in an Enzyme Inhibition ex Vivo Model▽

Cited by 40 publications

References 14 publications

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

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

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

11β-Hydroxysteroid Dehydrogenase Type 1 and the Metabolic Syndrome

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Product

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Discovery of Novel, Potent Benzamide Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Exhibiting Oral Activity in an Enzyme Inhibition ex Vivo Model^▽