Synthesis and optimization of arylsulfonylpiperazines as a novel class of inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

Sun, Daqing; Wang, Zhong Lin; Cardozo, Mario; Choi, Rebekah; DeGraffenreid, Michael; Di, Yongmei; He, Xiao; Jaén, Juan C.; Labelle, Marc; Liu, Jinsong; Ma, Ji; Miao, Shichang; Sudom, Athena; Tang, Liang; Tu, Hua; Ursu, Stefania; Walker, Nigel; Yan, Xuelei; Ye, Qiuping; Powers, Jay P.

doi:10.1016/j.bmcl.2008.12.114

Cited by 25 publications

(16 citation statements)

References 20 publications

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“…For type 1 11β-HSD, inhibitor series include diverse scaffolds: triazoles (Merck-544) and azabicyclic sulphonamides developed by both Merck and Eli Lilly [76, 77]; pentanedioic acid diamides developed by Merck-Serono [78]; pyridinyl arylsulfonamides developed by Pfizer (PF-915275) [79]; (phenylsulfonamido-methyl)-nicotine and (phenylsulfonamido-methyl)-thiazole derivatives [80]; arylsulfonylpiperazines, piperdyl- and cyclo-benzamides developed by Amgen (Amgen 2922) [81–83]; thiazolones developed by Biovitrum (BVT-2733) [84]; 1,5-substituted-1 H -tetrazoles developed by the group at Edinburgh [85]; and adamantyl ethanones developed by Ipsen/Sterix [86]. Many of these have nM affinity for the target.…”

Section: Hsd Inhibitor Classesmentioning

confidence: 99%

Human hydroxysteroid dehydrogenases and pre-receptor regulation: Insights into inhibitor design and evaluation

Penning

2011

The Journal of Steroid Biochemistry and Molecular Biology

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Hydroxysteroid dehydrogenases (HSDs) represent a major class of NAD(P)(H) dependent steroid hormone oxidoreductases involved in the pre-receptor regulation of hormone action. This is achieved by HSDs working in pairs so that they can interconvert ketosteroids with hydroxysteroids resulting in a change in ligand potency for nuclear receptors. HSDs belong to two protein superfamilies the aldo-keto reductases and the short-chain dehydrogenase/reductases. In humans, many of the important enzymes have been thoroughly characterized including the elucidation of their three-dimensional structures. Because these enzymes play fundamental roles in steroid hormone action they can be considered to be drug targets for a variety of steroid driven diseases: e.g. metabolic syndrome and obesity, inflammation, and hormone dependent malignancies of the endometrium, prostate and breast. This article will review how fundamental knowledge of these enzymes can be exploited in the development of isoform specific HSD inhibitors from both protein superfamilies.

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Section: Hsd Inhibitor Classesmentioning

confidence: 99%

Human hydroxysteroid dehydrogenases and pre-receptor regulation: Insights into inhibitor design and evaluation

Penning

2011

The Journal of Steroid Biochemistry and Molecular Biology

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“…Although CH 2 F and CF 2 H moieties can be installed from the corresponding halides, such procedures are inconvenient because they often require an excess of gaseous reagents. The synthesis of additional tertiary fluorides ( 62 and 63 ) was similarly achieved, presenting a useful alternative to traditional tertiary fluoride synthesis from the corresponding tertiary alcohol and treatment with diethylaminosulfur trifluoride (DAST; a highly toxic and dangerous reagent), a transformation that often proceeds in low yield (26). A current limitation is that the trifluoromethyl group cannot be readily installed with this method ( 64 ).…”

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confidence: 99%

Modular radical cross-coupling with sulfones enables access to sp ³ -rich (fluoro)alkylated scaffolds

Merchant

Edwards

Qin

et al. 2018

Science

191

119

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Cross-coupling chemistry is widely applied to carbon-carbon bond formation in the synthesis of medicines, agrochemicals, and other functional materials. Recently, single-electron-induced variants of this reaction class have proven particularly useful in the formation of C(sp)-C(sp) linkages, although certain compound classes have remained a challenge. Here, we report the use of sulfones to activate the alkyl coupling partner in nickel-catalyzed radical cross-coupling with aryl zinc reagents. This method's tolerance of fluoroalkyl substituents proved particularly advantageous for the streamlined preparation of pharmaceutically oriented fluorinated scaffolds that previously required multiple steps, toxic reagents, and nonmodular retrosynthetic blueprints. Five specific sulfone reagents facilitate the rapid assembly of a vast set of compounds, many of which contain challenging fluorination patterns.

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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.…”

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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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Synthesis and optimization of arylsulfonylpiperazines as a novel class of inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

Cited by 25 publications

References 20 publications

Human hydroxysteroid dehydrogenases and pre-receptor regulation: Insights into inhibitor design and evaluation

Human hydroxysteroid dehydrogenases and pre-receptor regulation: Insights into inhibitor design and evaluation

Modular radical cross-coupling with sulfones enables access to sp ³ -rich (fluoro)alkylated scaffolds

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

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Synthesis and optimization of arylsulfonylpiperazines as a novel class of inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

Cited by 25 publications

References 20 publications

Human hydroxysteroid dehydrogenases and pre-receptor regulation: Insights into inhibitor design and evaluation

Human hydroxysteroid dehydrogenases and pre-receptor regulation: Insights into inhibitor design and evaluation

Modular radical cross-coupling with sulfones enables access to sp 3 -rich (fluoro)alkylated scaffolds

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

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Modular radical cross-coupling with sulfones enables access to sp ³ -rich (fluoro)alkylated scaffolds