N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275

Siu, Michael; Johnson, Theodore; Wang, Yong; Nair, Sajiv K.; Taylor, Wayne E.; Cripps, Stephan J.; Matthews, Jean; Edwards, Martin P.; Pauly, T.A.; Ermolieff, Jacques; Castro, Arturo; Hosea, Natilie; LaPaglia, Amy; Fanjul, Andrea; Vogel, Jennifer E.

doi:10.1016/j.bmcl.2009.05.011

Cited by 42 publications

(32 citation statements)

References 41 publications

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“…The sulfonamide moiety contacts S170, V171, A172, Y177, G216 and L217. The chlorine of the chloromethylphenyl group pushes up against Y231 with the ring stacking with Y177 and making contact with I182 and L217 [30].…”

Section: Cofactor Bindingmentioning

confidence: 99%

“…Compound 5 (Pfizer) is selective for human 11β-HSD1 with K i <1 nM as opposed to K i = 750 nM for the mouse enzyme [30]. This difference between human and rodent enzymes is reflected in cellular assays where the EC 50 for HEK293 cells is 5 nM but for rat hepatoma cells is 14,500 nM.…”

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confidence: 99%

“…In rodents, 11β-HSD1 catalyzes the reduction of 11-dehydrocorticosterone (1b) to corticosterone (2b; Figure 1). There are two structures of the mouse protein available (Table 1) [49] and three structures of the guinea pig protein (Table 1) [30,50,51]. One of the mouse structures has a ligand in the substrate binding site (2b), as does one of the guinea pig structures (27).…”

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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: Cofactor Bindingmentioning

confidence: 99%

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confidence: 99%

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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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“…6,7) These data suggest that 11b-HSD1 could be a drug target for the treatment of metabolic syndrome as well as type 2 diabetes. During the last few years, small molecule 11b-HSD1 inhibitors have been reported, [8][9][10][11][12][13] and several candidates including Incyte's compound are in clinical trials.…”

mentioning

confidence: 99%

Identification of Cyclicsulfonamide Derivatives with an Acetamide Group as 11.BETA.-Hydroxysteroid Dehydrogenase 1 Inhibitors

Kim

Kwon

Chu

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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In the continuation of our 11b b-hydroxysteroid dehydrogenase type 1 (11b b-HSD1) inhibitor research, cyclic sulfonamide derivatives with an acetamide group at the 2-position were synthesized and evaluated for their abilities to inhibit 11b b-HSD1. Among this series, Compound 34 showed good in vitro activity toward human 11b b-HSD1, selectivity against 11b b-HSD2, microsomal stability, good pharmacokinetic and safety profiles human ether-a-go-go related gene (hERG and cytochrome P450 (CYP)). Also, a docking study explained the activity difference between human and mouse 11b b-HSD1.

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“…Liu et al, 2011;Morgan et al, 2009;Morgan & Tomlinson, 2010;Morton, 2010;Park et al, 2011;Rosenstock et al, 2010;U. Shah et al, 2010;Siu et al, 2009;Stewart & Tomlinson, 2009;Tiwari, 2010;Tu et al, 2008;van Raalte et al, 2009;Véniant et al, 2010;S. J. Wang et al, 2006;Webster et al, 2010;Yuan et al, 2007;X.…”

Section: β-Hsd1 Inhibition Studiesunclassified

11β-Hydroxysteroid Dehydrogenase Type 1 and the Metabolic Syndrome

Pereira¹,

Martins²,

Azevedo³

et al. 2011

Steroids - Clinical Aspect

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N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275

Cited by 42 publications

References 41 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

Identification of Cyclicsulfonamide Derivatives with an Acetamide Group as 11.BETA.-Hydroxysteroid Dehydrogenase 1 Inhibitors

11β-Hydroxysteroid Dehydrogenase Type 1 and the Metabolic Syndrome

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