Discovery and Initial SAR of Arylsulfonylpiperazine Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1)

Sun, Daqing; Wang, Zhong Lin; Di, Yongmei; Jaén, Juan C.; Labelle, Marc; Ma, Ji; Miao, Shichang; Sudom, Athena; Tang, Liang; Tomooka, Craig S.; Tu, Hua; Ursu, Stefania; Walker, Nigel; Yan, Xuelei; Ye, Qiuping; Powers, Jay P.

doi:10.1016/j.bmcl.2008.05.025

Cited by 34 publications

(7 citation statements)

References 15 publications

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“…The 3CZR_b structure also has CHAPS in the substrate binding site [42]. The interactions of the ligand with the protein are similar to those seen in the 1XU7 and 1XU9 structures.…”

Section: Xu7-therementioning

confidence: 59%

“…The nitrophenyl group projects to the surface of the protein through a gap between residues L126, P178, M179, V227 and M233. The 3CZR structure is one of four to contain a ligand with a core of (R)-2-methyl-1-(phenylsulfonyl)piperazine, the others being 3D4N, 3HFG and 3H6K [42].…”

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

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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“…The 3CZR_b structure also has CHAPS in the substrate binding site [42]. The interactions of the ligand with the protein are similar to those seen in the 1XU7 and 1XU9 structures.…”

Section: Xu7-therementioning

confidence: 59%

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

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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“…Some naphthalene arylsulfonyl-piperazines were identified as inhibitors of activated coagulation factor X (39) and human 11␤-hydroxysteroid dehydrogenase type 1 (40). Limited biological data have been reported for the phenylsulfonamide-pyrrolopyridine class of W1282X potentiators.…”

Section: Discussionmentioning

confidence: 99%

Correctors and Potentiators Rescue Function of the Truncated W1282X-Cystic Fibrosis Transmembrane Regulator (CFTR) Translation Product

Haggie

Phuan

Tan

et al. 2017

Journal of Biological Chemistry

111

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Edited by Thomas Sö llnerW1282X is the fifth most common cystic fibrosis transmembrane regulator (CFTR) mutation that causes cystic fibrosis. Here, we investigated the utility of a small molecule corrector/ potentiator strategy, as used for ⌬F508-CFTR, to produce functional rescue of the truncated translation product of the W1282X mutation, CFTR 1281 , without the need for readthrough. In transfected cell systems, certain potentiators and correctors, including VX-809 and VX-770, increased CFTR 1281 activity. To identify novel correctors and potentiators with potentially greater efficacy on CFTR 1281 , functional screens were done of ϳ30,000 synthetic small molecules and drugs/nutraceuticals in CFTR 1281 -transfected cells. Corrector scaffolds of 1-arylpyrazole-4-arylsulfonyl-piperazine and spiro-piperidine-quinazolinone classes were identified with up to ϳ5-fold greater efficacy than VX-809, some of which were selective for CFTR 1281 , whereas others also corrected ⌬F508-CFTR. Several novel potentiator scaffolds were identified with efficacy comparable with VX-770; remarkably, a phenylsulfonamide-pyrrolopyridine acted synergistically with VX-770 to increase CFTR 1281 function ϳ8-fold over that of VX-770 alone, normalizing CFTR 1281 channel activity to that of wild type CFTR. Corrector and potentiator combinations were tested in primary cultures and conditionally reprogrammed cells generated from nasal brushings from one W1282X homozygous subject. Although robust chloride conductance was seen with correctors and potentiators in homozygous ⌬F508 cells, increased chloride conductance was not found in W1282X cells despite the presence of adequate transcript levels. Notwithstanding the negative data in W1282X cells from one human subject, we speculate that corrector and potentiator combinations may have therapeutic efficacy in cystic fibrosis caused by the W1282X mutation, although additional studies are needed on human cells from W1282X subjects.

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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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Discovery and Initial SAR of Arylsulfonylpiperazine Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1)

Cited by 34 publications

References 15 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

Correctors and Potentiators Rescue Function of the Truncated W1282X-Cystic Fibrosis Transmembrane Regulator (CFTR) Translation Product

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

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