Discovery of adamantane ethers as inhibitors of 11β-HSD-1: Synthesis and biological evaluation

Patel, Jyoti; Qi, Shuai; Dinges, Jürgen; Winn, Martin; Pliushchev, Marina; Fung, Steven; Monzon, Katina; Chiou, William J.; Wang, Jiahong; Pan, Liping; Wagaw, Seble; Engstrom, Kenneth M.; Kerdesky, Francis A. J.; Longenecker, K.L.; Judge, Russell A.; Qin, Wenying; Imade, Hovis; Stolarik, DeAnne; Beno, David W. A.; Brune, Michael E.; Chovan, Linda E.; Sham, Hing L.; Jacobson, Peer B.; Link, J. T.

doi:10.1016/j.bmcl.2006.10.074

Cited by 40 publications

(31 citation statements)

References 16 publications

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“…A series of novel adamantyl ethanone compounds was identified as potent inhibitors of human 11b-HSD1. The most active compounds identified (52, 62, 72, 92, 103 and 104) display potent inhibition of 11b-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.…”

Section: Introductionmentioning

confidence: 98%

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: Introductionmentioning

confidence: 98%

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%

“…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%

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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“…Inhibition of human and mouse 11β-HSD1 and 11β-HSD2 enzymatic activity was determined through scintillation proximity assay (SPA), using microsomes containing 11β-HSD1 or 11β-HSD2. [12][13][14][15][16] Enoxolone was used as a positive control. The human and murine 11β-HSD1 and 11β-HSD2 enzymes were expressed in HEK-293 cells.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, an X-ray crystal structure (PDB code 3FCO) satisfactory for structure-based molecular modeling has been released. 13 This X-ray structure consists of a complex of human 11β-HSD1 with a potent synthetic inhibitor and with the co-substrate nicotinamide adenine dinucleotide phosphate (NADP). The interactions of the inhibitor with 11β-HSD1 and NADP could be interpreted in a very specific way by building a PCM.…”

Section: 10mentioning

confidence: 99%

Discovery of Novel 11β-HSD1 Inhibitors by Pharmacophore-Based Virtual Screening

Kim¹,

Lee²,

Han³

et al. 2012

Bulletin of the Korean Chemical Society

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The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme is involved in modulation of glucocorticoid activity within target tissues. This enzyme may contribute to obesity and/or metabolic disease through its action in adipose or liver tissue. Inhibition of 11β-HSD1 has major therapeutic potential for glucocorticoidassociated diseases, including obesity, diabetes (wound healing), and muscle atrophy. To develop such therapeutics, we performed a pharmacophore-based virtual screening (VS) for identification of novel 11β-HSD1 inhibitors and found that the VS hit compounds show potent inhibition of 11β-HSD1 enzyme activity. Further, we present a binding model for active compounds. The proposed pharmacophore may serve as a useful guideline for future design of new chemical entities as 11β-HSD1-targeted antidiabetic agents.

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Discovery of adamantane ethers as inhibitors of 11β-HSD-1: Synthesis and biological evaluation

Cited by 40 publications

References 16 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

Discovery of Novel 11β-HSD1 Inhibitors by Pharmacophore-Based Virtual Screening

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