Discovery and Metabolic Stabilization of Potent and Selective 2-Amino-<i>N</i>-(adamant-2-yl) Acetamide 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Rohde, Jeffrey J.; Pliushchev, Marina; Sorensen, Bryan K.; Wódka, Dariusz; Qi, Shuai; Wang, Jiahong; Fung, Steven; Monzon, Katina; Chiou, William J.; Pan, Liping; Deng, X.Q.; Chovan, Linda E.; Ramaiya, Atul; Mullally, Mark M.; Henry, Rodger F.; Stolarik, DeAnne; Imade, Hovis; Marsh, Kennan C.; Beno, David W. A.; Fey, Thomas A.; Droz, Brian A.; Brune, Michael E.; Camp, Heidi S.; Sham, Hing L.; Frevert, Ernst U.; Jacobson, Peer B.; Link, J. T.

doi:10.1021/jm0609364

Cited by 76 publications

(37 citation statements)

References 72 publications

(76 reference statements)

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“…Since 11b-HSD2 inhibition leads to high blood pressure, isoform specificity is a key consideration in the design of 11b-HSD inhibitors. Non-steroidal adamantyl-based inhibitors 36b and 36c have been shown to inhibit 11b-HSD1 above 11b-HSD2 by factors of 350-fold (human) or 15,000-fold (rat), respectively [158,159]. The monohydroxylated adamantyl group of 36b delivered a compound with increased metabolic stability in mouse and human liver microsomes, relative to the unsubstituted adamantyl-based analogue [158].…”

Section: Anti-hypertensive and Anti-inflammatory Agentsmentioning

confidence: 99%

“…In mice, 35 was converted to the 3 0 -hydroxylated adamantyl derivative, which was similar in activity to the parent compound [154]. Microsomal degradation of a compound of type 36e36c class produced the bridgehead monohydroxylated derivative as the major product and a dihydroxylated derivative as the minor product [158]. To investigate the metabolic hydroxylation of the adamantyl group, the three bridgehead hydrogen atoms in adamantyl-1-carboxylic acid were substituted with fluorine atoms [179].…”

Section: Metabolism Of Adamantyl-based Compoundsmentioning

confidence: 99%

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The many faces of the adamantyl group in drug design

Liu

Obando

Liao

et al. 2011

European Journal of Medicinal Chemistry

262

172

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Section: Anti-hypertensive and Anti-inflammatory Agentsmentioning

confidence: 99%

Section: Metabolism Of Adamantyl-based Compoundsmentioning

confidence: 99%

The many faces of the adamantyl group in drug design

Liu

Obando

Liao

et al. 2011

European Journal of Medicinal Chemistry

262

172

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“…Compound 3 (Abbott; Figure 2) inhibits human 11β-HSD1 with K i = 5 nM and the mouse and rat enzymes with K i = 15 nM and 4 nM, respectively [28]. Inhibition of 11β-HSD2 from all three species is poor (K i >100 μM).…”

mentioning

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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“…The first three compounds in Table 1 exhibit higher potency for rat 11b-HSD1 than the human enzyme (Richards et al 2006). The other three compounds, however, have higher potency for human 11b-HSD1 than the mouse enzyme (Rohde et al 2007;Sorensen et al 2006;St Jean et al 2007). Not all 11b-HSD1 inhibitors have species selectivity with respect to human and rodent activities; there are many compounds with comparable human and rodent potency values.…”

Section: Studies With Selective 11b-hsd1 Inhibitorsmentioning

confidence: 97%

Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 in Antidiabetic Therapy

Wang

2011

Diabetes - Perspectives in Drug Therapy

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Glucocorticoid action is mediated by glucocorticoid receptor (GR), which upon cortisol binding is activated and regulates the transcriptional expression of target genes and downstream physiological functions. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol. Since cortisol is also produced through biosynthesis in the adrenal glands, the total cortisol level in a given tissue is determined by both the circulating cortisol concentration and the local 11β-HSD1 activity. 11β-HSD1 is expressed in liver, adipose, brain, and placenta. Since it contributes to the local cortisol levels in these tissues, 11β-HSD1 plays a critical role in glucocorticoid action. The metabolic symptoms caused by glucocorticoid excess in Cushing's syndrome overlap with the characteristics of the metabolic syndrome, suggesting that increased glucocorticoid activity may play a role in the etiology of the metabolic syndrome. Consistent with this notion, elevated adipose expression of 11β-HSD1 induced metabolic syndrome-like phenotypes in mice. Thus, 11β-HSD1 is a proposed therapeutic target to normalize glucocorticoid excess in a tissue-specific manner and mitigate obesity and insulin resistance. Selective inhibitors of 11β-HSD1 are under development for the treatment of type 2 diabetes and other components of the metabolic syndrome.

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Discovery and Metabolic Stabilization of Potent and Selective 2-Amino-N-(adamant-2-yl) Acetamide 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Cited by 76 publications

References 72 publications

The many faces of the adamantyl group in drug design

The many faces of the adamantyl group in drug design

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

Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 in Antidiabetic Therapy

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