β-Keto sulfones as inhibitors of 11β-hydroxysteroid dehydrogenase type I and the mechanism of action

Xiang, Jason; Ipek, Manus; Suri, Vipin; Tam, May; Xing, Yuzhe; Huang, Nelson; Zhang, Yanling; Tobin, James F.; Mansour, Tarek S.; McKew, John C.

doi:10.1016/j.bmc.2007.04.035

Cited by 97 publications

(60 citation statements)

References 22 publications

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“…The mechanistic study from Wyeth suggested that a known 11b-HSD1 inhibitor with a b-keto sulfone linker is a substrate of the enzyme. [59] Our compounds with a ketone group in the same approximate region may also act as substrates; however, we have not tested this hypothesis.…”

Section: Discussionmentioning

confidence: 95%

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: Discussionmentioning

confidence: 95%

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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“…19)). Xiang et al 254 of Wyeth discovered b-keto sulfones that were shown to be potent and selective 11b-HSD1 inhibitors such as (112) (Fig. 19), 11b-HSD1 (IC 50 ¼ 0.06 mM), 11b-HSD2 (IC 50 > 200 mM) versus 1.5 mM for (113) (Fig.…”

Section: Beta-hydroxysteroid Dehydrogenase Type 1 (11b-hsd1) Inhibimentioning

confidence: 96%

Recent and emerging anti‐diabetes targets

Mohler

et al. 2008

Medicinal Research Reviews

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Diabetes is a disease that affects over 150 million people worldwide for which there are multiple oral and injectable medications. Because of trends in obesity and sedentary lifestyles, diabetes rates in both developed and developing countries are increasing at an alarming rate. Current medications are not adequately effective in maintaining long-term glycemic control in most patients, even when used in combination, leaving diabetics susceptible to developing life threatening and debilitating complications such as cardiovascular disease, blindness, kidney complications, and amputations. Consequently, there is a critical need for more potent pharmacotherapies with novel mechanisms of action. A panel of 20 emerging diabetes targets is presented, and small molecule modulators for each target will be discussed.

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“…In addition, b-keto sulfones have gained wide applications as starting materials in the synthesis of several important compounds [8][9][10].Incontinuation of our interests in the chemistry and biologically activity of sulfone and sulfonamide derivatives [11][12][13][14][15][16], we report herein the synthesis and X-ray single crystal analyses of the title compound. Fortunately,wehavesucceeded to getsinglecrystals of thetitle compoundand were able to assign its(E)-configuration.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of (E)-3-(4-methoxyphenyl)-1-(thiophen-2-yl)-2- tosylprop-2-en-1-one, C21H18O4S2

Abdel‐Aziz

Ghabbour

Fun

2015

Zeitschrift Für Kristallographie - New Crystal Structures

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Source of material 1-(Thiophen-2-yl)-2-tosylethan-1-one waspreparedbythe reaction of 2-bromo-1-(thiophen-2-yl)ethan-1-one with sodium 4-tolylsulfinate.N ext, ther eaction of 1-(thiophen-2-yl)-2-tosylethan-1-one with 4-anisaldehyde, in the presence of piperidine, afforded the title compound in 77% yield. The IR revealed the absorption band of ac arbonyl function at 1665 cm -1 while its 1 HNMR exhibited the signal of -CH= group at d =8.01 in addition to the singlet signals of methyl and methoxyprotons at d = 2.40and 3.74, respectively. DiscussionThere are great interests in the chemistry and biological activity of thiophenederivativesasthe thiophenemoiety is an important domain in alarge number of biologically active structures [1][2][3][4], and it is also awell-known isostere for benzene ring [5].Onthe other hand, sulfones received aspecial interest in organic chemistry for their ambivalent nature and due to their versatile reactivity in organic synthesis [6, 7]. In addition, b-keto sulfones have gained wide applications as starting materials in the synthesis of several important compounds [8][9][10].Incontinuation of our interests in the chemistry and biologically activity of sulfone and sulfonamide derivatives [11][12][13][14][15][16], we report herein the synthesis and X-ray single crystal analyses of the title compound. Fortunately,wehavesucceeded to getsinglecrystals of thetitle compoundand were able to assign its(E)-configuration. Thecrystal structure contains onem olecule in the asymmetric unit. The E isomerofthe title compound is the kinetically favored candidate. The double bond of C6=C7 is characterized by the distance of 1.334 (4) Å. Themolecules packing in the crystal structure is stabilized by two weak intermolecular interactions, with O3 and O4 as hydrogen bond acceptors and C3 and C19 as hydrogen bond donor. The distance of the interactions between H3A×××O3 is 2.4400(11) Å, H19A×××O4 is 2.4700(9) Åa nd the angles C3-H3A×××O3 is 123.00(4)°, C19-H19A×××O4 is 166.00(7)°. Z. Kristallogr.

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β-Keto sulfones as inhibitors of 11β-hydroxysteroid dehydrogenase type I and the mechanism of action

Cited by 97 publications

References 22 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

Recent and emerging anti‐diabetes targets

Crystal structure of (E)-3-(4-methoxyphenyl)-1-(thiophen-2-yl)-2- tosylprop-2-en-1-one, C21H18O4S2

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