Phenylcyclobutyl triazoles as selective inhibitors of 11β-hydroxysteroid dehydrogenase type I

Zhu, Yang; Olson, Steven H.; Graham, Donald W.; Patel, Gool F.; Hermanowski‐Vosatka, Anne; Mundt, Steven S.; Shah, Kashmira; Springer, Marty S.; Thieringer, Rolf; Wright, Samuel D.; Xiao, Jianying; Zokian, Hratch; Dragovic, Jasminka; Balkovec, James M.

doi:10.1016/j.bmcl.2008.04.014

Cited by 48 publications

(36 citation statements)

References 19 publications

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“…Benzyl amide (11) showed a good in vitro activity with an IC 50 value of 174 nM. Whereas, heteroaryl amides (12, 13) were found to be less potent.…”

Section: Resultsmentioning

confidence: 99%

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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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“…Benzyl amide (11) showed a good in vitro activity with an IC 50 value of 174 nM. Whereas, heteroaryl amides (12, 13) were found to be less potent.…”

Section: Resultsmentioning

confidence: 99%

“…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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“…Zhu et al demonstrated that 3-(phenylcyclobutyl)-1,2,4-triazole derivatives (24) show reduction in the blood glucose and lipid levels by the inhibition of 11β-hydroxysteroid dehydrogenase type I (11β-HSDI) [68]. On the basis of a lead structure from high throughput screening, they identified methyl-phenyl-carbamoyl-triazoles as potent and efficacious HSL inhibitors to show their antidiabetic activity [69].…”

Section: Antidiabetic Activitymentioning

confidence: 99%

Pharmacological significance of triazole scaffold

Kharb

Sharma

Yar

2010

Journal of Enzyme Inhibition and Medicinal Chemistry

483

236

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“…In a mouse model of obesity (the diet-induced obese mouse), animals treated with MK-0916 (compound 5a in reference [13]) for 9 days lost an average of 5% of bodyweight relative to control animals; studies with MK-0916 in streptozotocin-induced diabetic mice on a high-fat diet (a model for type 2 diabetes) produced evidence for antihyperglycaemic activity, and in the murine apoE model of atherosclerosis, plaque size was significantly reduced compared with placebo in animals treated for 8 weeks with MK-0916 (A. Hermanowski-Vosatka unpublished data). Clinical trials with this compound have produced mixed results, however.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic–pharmacodynamic studies of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor MK‐0916 in healthy subjects

Wright

Stone

Crumley

et al. 2013

Brit J Clinical Pharma

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AIMSTo characterize pharmacokinetic parameters of MK-0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable-isotope labelling) the in vivo inhibition of cortisone-to-cortisol conversion following oral MK-0916. METHODSData are presented from two randomized, controlled, double-blind, rising-dose phase I studies. In the first study, subjects received single oral doses of 0.4-100 mg MK-0916 (n = 16). In the second study, subjects received 0.2-225 mg MK-0916 followed by daily doses of 0.2-100 mg for 13 days beginning on day 2 or day 15 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [13 C4]cortisol were measured by high-pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [ 13 C4]cortisone. RESULTSDoses Ն3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1-1.8 h). Exposure (measured as the area under the concentration-time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK-0916 once daily for 14 days, the mean trough plasma concentration was 240 nM and in vivo cortisone-to-cortisol conversion was inhibited by 84%. The relationship between plasma MK-0916 and hepatic 11b-hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple Emax model with an IC50 of 70.4 nM. Exposure to MK-0916 was generally well tolerated. CONCLUSIONSThese findings indicate that 11b-hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK-0916 that are well tolerated. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The intracellular enzyme 11b-hydroxysteroid dehydrogenase type 1 converts the inactive glucocorticoid cortisone into the active hormone cortisol in many tissues, including the liver and adipocytes. It is thought that increased conversion of cortisone to cortisol contributes to pathophysiology associated with the metabolic syndrome.• MK-0916 is an inhibitor of 11b-hydroxysteroid dehydrogenase type 1 that has been evaluated clinically as a potential therapy for type 2 diabetes, obesity or hypertension. WHAT THIS STUDY ADDS• In lean, healthy male subjects, MK-0916 was well tolerated when given in oral doses that were sufficient to provide profound inhibition of hepatic conversion of cortisone to cortisol.• Multiple-dose administration of 6 mg day -1 MK-0916 provided mean plasma concentrations >200 nM at all times, a plasma drug concentration that inhibited systemic 11b-hydroxysteroid dehydrogenase type 1 by 84%.

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Phenylcyclobutyl triazoles as selective inhibitors of 11β-hydroxysteroid dehydrogenase type I

Cited by 48 publications

References 19 publications

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

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

Pharmacological significance of triazole scaffold

Pharmacokinetic–pharmacodynamic studies of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor MK‐0916 in healthy subjects

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