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Shu-Chen Lu,
Larissa Atangan,
Ki Won Kim,
Michelle M Chen,
Renee Komorowski,
Carolyn Chu,
Joon Han,
Sylvia Hu,
Wei Gu,
Murielle Véniant, Minghan Wang
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ABSTRACT: The aim of this study is to investigate the capability of an apoA-I mimetic with multiple amphipathic helices to form HDL-like particles in vitro and in vivo. To generate multivalent helices and to track the peptide mimetic, we have constructed a peptibody by fusing two tandem repeats of 4F peptide to the C terminus of a murine IgG Fc fragment. The resultant peptidbody, mFc-2X4F, dose-dependently promoted cholesterol efflux in vitro, and the efflux potency was superior to monomeric 4F peptide. Like apoA-I, mFc-2X4F stabilized ABCA1 in J774A.1 and THP1 cells. The peptibody formed larger HDL particles when incubated with cultured cells compared with those by apoA-I. Interestingly, when administered to mice, mFc-2X4F increased both pre-β and α-1 HDL subfractions. The lipid-bound mFc-2X4F was mostly in the α-1 migrating subfraction. Most importantly, mFc-2X4F and apoA-I were found to coexist in the same HDL particles formed in vivo. These data suggest that the apoA-I mimetic peptibody is capable of mimicking apoA-I to generate HDL particles. The peptibody and apoA-I may work cooperatively to generate larger HDL particles in vivo, either at the cholesterol efflux stage and/or via fusion of HDL particles that were generated by the peptibody and apoA-I individually.
The Journal of Lipid Research 01/2012; 53(4):643-52. · 5.56 Impact Factor
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Junming Yie,
Wei Wang,
Liying Deng,
Lei-Ting Tam,
Jennitte Stevens,
Michelle M Chen,
Yang Li,
Jing Xu,
Richard Lindberg,
Randy Hecht,
Murielle Véniant,
Ching Chen, Minghan Wang
[show abstract]
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ABSTRACT: The endocrine fibroblast growth factor 21 (FGF21) requires both fibroblast growth factor receptor (FGFR) and β-Klotho for signaling. In this study, we sought to understand the inter-molecular physical interactions in the FGF21/FGFR/β-Klotho complex by deleting key regions in FGFR1c or FGF21. Deletion of the D1 and the D1-D2 linker (the D1/linker region) from FGFR1c led to β-Klotho-independent receptor activation by FGF21, suggesting that there may be a direct interaction between FGF21 and the D1/linker region-deficient FGFR1c. Consistent with this, the extracellular portion of FGFR1c lacking the D1/linker region blocked FGF21 action in a reporter assay, presumably by binding to and sequestering FGF21 from acting on cell surface receptor complex. In addition, the D1/linker region-deficient FGFR1c had enhanced interaction with β-Klotho. Further, we demonstrated that deletion of the D1/linker region enhanced the formation of the FGF21/β-Klotho/FGFR1c ternary complex in both Biacore and asymmetrical flow field flow fractionation studies. Finally, we found that the N-terminus of FGF21 is involved in the interaction with FGFR1c and FGF21/β-Klotho/FGFR1c ternary complex formation. Taken together, our data suggest that the D1/linker region regulates both the FGF21/FGFR1c and FGFR1c/β-Klotho interaction, and a direct interaction of FGF21 with FGFR1c may be an important step in receptor-mediated FGF21 signaling.
Chemical Biology & Drug Design 01/2012; 79(4):398-410. · 2.28 Impact Factor
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ABSTRACT: Circulating levels of fibroblast growth factor 21 (FGF21), a metabolic regulator of glucose, lipid, and energy homeostasis, are elevated in obese diabetic subjects, raising questions about potential FGF21 resistance. Here we report tissue expression changes in FGF21 and its receptor components, and we describe the target-organ and whole-body responses to FGF21 in ob/ob and diet-induced obese (DIO) mice. Plasma FGF21 concentrations were elevated 8- and 16-fold in DIO and ob/ob mice, respectively, paralleling a dramatic increase in hepatic FGF21 mRNA expression. Concurrently, expression levels of βKlotho, FGF receptor (FGFR)-1c, and FGFR2c were markedly down-regulated in the white adipose tissues (WAT) of ob/ob and DIO mice. However, dose-response curves of recombinant human FGF21 (rhFGF21) stimulation of ERK phosphorylation in the liver and WAT were not right shifted in disease models, although the magnitude of induction in ERK phosphorylation was partially attenuated in DIO mice. Whole-body metabolic responses were preserved in ob/ob and DIO mice, with disease models being more sensitive and responsive than lean mice to the glucose-lowering and weight-loss effects of rhFGF21. Endogenous FGF21 levels, although elevated in diseased mice, were below the half-maximal effective concentrations of rhFGF21, suggesting a state of relative deficiency. Hepatic and WAT FGF21 mRNA expression levels declined after rhFGF21 treatment in the absence of the increased expression levels of βKlotho and FGFR. We conclude that overt FGF21 resistance was not evident in the disease models, and increased hepatic FGF21 expression as a result of local metabolic changes is likely a major cause of elevated circulating FGF21 levels.
Endocrinology 11/2011; 153(1):69-80. · 4.46 Impact Factor
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John P Gibbs,
Maurice G Emery,
Ian McCaffery,
Brian Smith,
Megan A Gibbs,
Anna Akrami,
John Rossi,
Katherine Paweletz,
Marc R Gastonguay,
Edgar Bautista, Minghan Wang,
Riccardo Perfetti,
Oranee Daniels
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ABSTRACT: Inhibition of 11β-HSD1 is hypothesized to improve measures of insulin sensitivity and hepatic glucose output in patients with type II diabetes. AMG 221 is a potent, small molecule inhibitor of 11β-HSD1. The objective of this analysis is to describe the pharmacokinetic/pharmacodynamic (PK/PD) relationship between AMG 221 and 11β-HSD1 inhibition in ex vivo adipose tissue samples. Healthy, obese subjects were administered a single dose of 3, 30, or 100 mg of oral AMG 221 (n = 44) or placebo (n = 11). Serial blood samples were collected over 24 hours. Subcutaneous adipose tissue samples were collected by open biopsy. Population PK/PD analysis was conducted using NONMEM. The inhibitory effects (mean ± standard error of the estimate) of AMG 221 on 11β-HSD1 activity were directly related to adipose concentrations with I(max) (the maximal inhibition of 11β-HSD1 activity) and IC₅₀ (the plasma AMG 221 concentration associated with 50% inhibition of enzyme activity) of 0.975 ± 0.003 and 1.19 ± 0.12 ng/mL, respectively. The estimated baseline 11β-HSD1 enzyme activity was 755 ± 61 pmol/mg. An equilibration rate constant (k(eo)) of 0.220 ± 0.021 h⁻¹ described the delay between plasma and adipose tissue AMG 221 concentrations. AMG 221 potently blocked 11β-HSD1 activity, producing sustained inhibition for the 24-hour study duration as measured in ex vivo adipose samples. Early characterization of concentration-response relationships can support rational selection of dose and regimen for future studies.
The Journal of Clinical Pharmacology 06/2011; 51(6):830-41. · 2.91 Impact Factor
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ABSTRACT: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the interconversion of inactive cortisone to active cortisol in a NADPH dependent manner. Excess cortisol or 11β-HSD1 leads to insulin resistance and metabolic syndrome. Inhibition of 11β-HSD1 activity has been pursued vigorously by the pharmaceutical industry as a potential therapeutic strategy for the treatment of type 2 diabetes. As a result, a large number of chemical classes have been identified as potent and selective small molecule inhibitors for 11β-HSD1. Here we review the recent progress in the discovery and development of small molecule inhibitors of 11β-HSD1 by highlighting the medicinal chemistry, SAR, in vivo pharmacodynamic effects and efficacy of a few representative classes of inhibitors in models of diabetes. Furthermore, we also review the structural characteristics of each class of inhibitors by analyzing the inhibitor co-crystal structures of 11β-HSD1.
Current topics in medicinal chemistry 04/2011; 11(12):1464-75. · 4.47 Impact Factor
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Minghan Wang
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ABSTRACT: Glucocorticoid action is mediated by glucocorticoid receptor (GR), which upon cortisol binding is activated and regulates the transcriptional expression of target genes and downstream physiological functions. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol. Since cortisol is also produced through biosynthesis in the adrenal glands, the total cortisol level in a given tissue is determined by both the circulating cortisol concentration and the local 11β-HSD1 activity. 11β-HSD1 is expressed in liver, adipose, brain, and placenta. Since it contributes to the local cortisol levels in these tissues, 11β-HSD1 plays a critical role in glucocorticoid action. The metabolic symptoms caused by glucocorticoid excess in Cushing's syndrome overlap with the characteristics of the metabolic syndrome, suggesting that increased glucocorticoid activity may play a role in the etiology of the metabolic syndrome. Consistent with this notion, elevated adipose expression of 11β-HSD1 induced metabolic syndrome-like phenotypes in mice. Thus, 11β-HSD1 is a proposed therapeutic target to normalize glucocorticoid excess in a tissue-specific manner and mitigate obesity and insulin resistance. Selective inhibitors of 11β-HSD1 are under development for the treatment of type 2 diabetes and other components of the metabolic syndrome.
Handbook of experimental pharmacology 01/2011;
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Paul E Harrington,
David J St Jean,
Jeffrey Clarine,
Thomas S Coulter,
Michael Croghan,
Adam Davenport,
James Davis,
Chiara Ghiron,
Jonathan Hutchinson,
Michael G Kelly, [......],
Elena Portero-Larragueta,
Jeff D Reagan,
Kelly A Regal,
Andrew Tasker, Minghan Wang,
Yuhua Yang,
Guomin Yao,
Qingping Zeng,
Charles Henley,
Christopher Fotsch
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ABSTRACT: The discovery of a series of novel and orally efficacious type II calcimimetics, developed from the lead compound 1, is described herein. Compound 22 suppressed plasma PTH levels relative to vehicle when dosed orally in a rat pharmacodynamic model.
Bioorganic & medicinal chemistry letters 09/2010; 20(18):5544-7. · 2.65 Impact Factor
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Murielle M Véniant,
Clarence Hale,
Randall W Hungate,
Kyung Gahm,
Maurice G Emery,
Janan Jona,
Smriti Joseph,
Jeffrey Adams,
Andrew Hague,
George Moniz, [......],
Michelle M Chen,
Rod Cupples,
Ki Won Kim,
David J St Jean,
Lars Johansson,
Martin A Henriksson,
Meredith Williams,
Jerk Vallgårda,
Christopher Fotsch, Minghan Wang
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ABSTRACT: Thiazolones with an exo-norbornylamine at the 2-position and an isopropyl group on the 5-position are potent 11beta-HSD1 inhibitors. However, the C-5 center was prone to epimerization in vitro and in vivo, forming a less potent diastereomer. A methyl group was added to the C-5 position to eliminate epimerization, leading to the discovery of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221). This compound decreased fed blood glucose and insulin levels and reduced body weight in diet-induced obesity mice.
Journal of Medicinal Chemistry 06/2010; 53(11):4481-7. · 4.80 Impact Factor
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ABSTRACT: Resveratrol is a plant polyphenol capable of exerting beneficial metabolic effects which are thought to be mediated in large by the activation of the NAD(+)-dependent protein deacetylase SIRT1. Although resveratrol has been claimed to be a bona fide SIRT1 activator using a peptide substrate (Fluor de Lys-SIRT1 peptide substrate), recent reports indicate that this finding might be an experimental artifact and need to be clarified. Here, we show that: (i) the Fluor de Lys-SIRT1 peptide is an artificial SIRT1 substrate because in the absence of the covalently linked fluorophore the peptide itself is not a substrate of the enzyme, (ii) resveratrol does not activate SIRT1 in vitro in the presence of either a p53-derived peptide substrate or acetylated PGC-1alpha isolated from cells, and (iii) although SIRT1 deacetylates PGC-1alpha in both in vitro and cell-based assays, resveratrol did not activate SIRT1 under these conditions. Based on these observations, we conclude that the pharmacological effects of resveratrol in various models are unlikely to be mediated by a direct enhancement of the catalytic activity of the SIRT1 enzyme. In consequence, our data challenge the overall utility of resveratrol as a pharmacological tool to directly activate SIRT1.
Chemical Biology & Drug Design 10/2009; 74(6):619-24. · 2.28 Impact Factor
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ABSTRACT: 11β-Hydroxysteroid dehydrogenase (11β-HSD1) is involved in glucocorticoid activation in a tissue-specific manner. In tissues and intact cells, it functions primarily as a reductase by converting inactive cortisone to cortisol. Since glucocorticoid action is implicated in the development of the metabolic syndrome, inhibition of 11β-HSD1 has been proposed as a therapeutic strategy to treat type 2 diabetes. 11β-HSD1 is a member of the short chain dehydrogenase/reductase (SDR) superfamily with the “Y183SASK187” sequence and Ser170 at the active site that matches the catalytic domain signature motif of “YXXXK” in SDRs. The recent success in the determination of various 11β-HSD1 3-dimentional structures has facilitated a higher level understanding of the interactions among the enzyme, the cofactor and the substrate as well as substrate site inhibitors. In particular, the structural analysis of 11β-HSD1 in complex with a non-selective inhibitor carbenoxolone (CBX) has advanced our knowledge of inhibitor-enzyme interactions. In addition to the catalytic triad, residues close to the steroid binding site and surrounding areas have been identified as important in stabilizing the substrate. These findings have accelerated medicinal chemistry efforts to discover selective 11β-HSD1 inhibitors in the pharmaceutical industry. A large number of chemical classes have been identified as potent and selective 11β-HSD1 inhibitors. Some common features in enzyme-inhibitor interactions were observed with structurally distinct compounds. Chemical class-specific interactions were discovered as well, which explain the structural diversity of selective 11β-HSD1 inhibitors. In this article, we review the structural characteristics of 11β-HSD1 enzymes in several species. By comparing active sites, substrate binding and subunit interactions, we have identified structural features and residues in the active site important for inhibitor binding. Further, through analysis of the major interactions between the active site residues and inhibitors of different chemical classes, we have determined compound class-specific structural requirements for optimal enzyme- inhibitor interaction.
Current Chemical Biology 04/2009; 3(2):159-170.
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Junming Yie,
Randy Hecht,
Jennifer Patel,
Jennitte Stevens,
Wei Wang,
Nessa Hawkins,
Shirley Steavenson,
Steve Smith,
Dwight Winters,
Seth Fisher,
Ling Cai,
Ed Belouski,
Ching Chen,
Mark L Michaels,
Yue-Sheng Li,
Richard Lindberg, Minghan Wang,
Murielle Véniant,
Jing Xu
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ABSTRACT: Fibroblast growth factor-21 (FGF21) signaling requires the presence of beta-Klotho, a co-receptor with a very short cytoplasmic domain. Here we show that FGF21 binds directly to beta-Klotho through its C-terminus. Serial C-terminal truncations of FGF21 weakened or even abrogated its interaction with beta-Klotho in a Biacore assay, and led to gradual loss of potency in a luciferase reporter assay but with little effect on maximal response. In contrast, serial N-terminal truncations of FGF21 had no impact on beta-Klotho binding. Interestingly, several of them exhibited characteristics of partial agonists with minimal effects on potency. These data demonstrate that the C-terminus of FGF21 is critical for binding to beta-Klotho and the N-terminus is critical for fibroblast growth factor receptor (FGFR) activation.
FEBS letters 01/2009; 583(1):19-24. · 3.54 Impact Factor
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Christopher Fotsch,
Michael D Bartberger,
Eric A Bercot,
Michelle Chen,
Rod Cupples,
Maury Emery,
Jenne Fretland,
Anil Guram,
Clarence Hale,
Nianhe Han, [......],
David J St Jean,
Stefania Ursu,
Murielle Véniant,
Guifen Xu,
Qiuping Ye,
Chester Yuan,
Jiandong Zhang,
Xiping Zhang,
Hua Tu, Minghan Wang
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ABSTRACT: A series of compounds containing the 2-amino-1,3-thiazol-4(5H)-one core were found to be potent inhibitors of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). One of our lead compounds from this series activated the human nuclear xenobiotic receptor, pregnane X receptor (PXR). To try and mitigate the PXR activity, we prepared analogues of our lead series that contained polar groups on the right-hand side of the thiazolone. Several analogues containing amides or alcohols appended to the C-5 position of the thiazolone showed a significant reduction in PXR activity. Through these structure-activity efforts, a compound containing a tert-alcohol group off the C-5 position, analogue (S)-33a, was found to have an 11beta-HSD1 Ki = 35 nM and negligible PXR activity. Compound (S)-33a was advanced into a pharmacodynamic model in cynomolgus monkeys, where it inhibited adipose 11beta-HSD1 activity after being orally administered.
Journal of Medicinal Chemistry 12/2008; 51(24):7953-67. · 4.80 Impact Factor
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Journal of Medicinal Chemistry 08/2008; 51(16):4851-7. · 4.80 Impact Factor
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ABSTRACT: Glucocorticoid action is linked to the development of obesity and insulin resistance. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been proposed as a strategy to suppress glucocorticoid action in a tissue-specific manner. A large variety of 11beta-HSD1 inhibitor classes are under investigation by the pharmaceutical industry to treat type 2 diabetes and obesity.
Mini Reviews in Medicinal Chemistry 07/2008; 8(7):702-10. · 2.53 Impact Factor
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Lars Johansson,
Christopher Fotsch,
Michael D Bartberger,
Victor M Castro,
Michelle Chen,
Maurice Emery,
Sonja Gustafsson,
Clarence Hale,
Dean Hickman,
Evert Homan, [......],
Aiwen Li,
Kenneth McRae,
George Moniz,
Guy Matsumoto,
Carlos Orihuela,
Gunnar Palm,
Murielle Veniant, Minghan Wang,
Meredith Williams,
Jiandong Zhang
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ABSTRACT: 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has attracted considerable attention during the past few years as a potential target for the treatment of diseases associated with metabolic syndrome. In our ongoing work on 11beta-HSD1 inhibitors, a series of new 2-amino-1,3-thiazol-4(5 H)-ones were explored. By inserting various cycloalkylamines at the 2-position and alkyl groups or spirocycloalkyl groups at the 5-position of the thiazolone, several potent 11beta-HSD1 inhibitors were identified. An X-ray cocrystal structure of human 11beta-HSD1 with compound 6d (Ki=28 nM) revealed a large lipophilic pocket accessible by substitution off the 2-position of the thiazolone. To increase potency, analogues were prepared with larger lipophilic groups at this position. One of these compounds, the 3-noradamantyl analogue 8b, was a potent inhibitor of human 11beta-HSD1 (Ki=3 nM) and also inhibited 11beta-HSD1 activity in lean C57Bl/6 mice when evaluated in an ex vivo adipose and liver cortisone to cortisol conversion assay.
Journal of Medicinal Chemistry 06/2008; 51(10):2933-43. · 5.25 Impact Factor
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ABSTRACT: Plasma or serum lipoprotein analysis is commonly carried out with a conventional size-exclusion fast-performance liquid chromatography method that requires large sample volumes (1-2 ml). To determine lipoprotein profiles of mice with this method, plasma or serum samples have to be pooled from a group of animals, which often requires sacrificing animals. Here we report an optimized anion-exchange chromatography method with simplified cholesterol collection and detection system. After 5-10 microl serum was injected for anion-exchange chromatography, a stepwise gradient was applied and fractions were collected on a 96-well plate. Cholesterol content in each well was measured using a fluorescence-based detection method. With this method, distinct lipoprotein peaks corresponding to high-density lipoprotein, low-density lipoprotein, and very-low-density lipoprotein, can be easily separated and identified with excellent resolution. The entire high-performance liquid chromatography run takes about 30min and the results are reproducible with a low variability. The small sample size allows analyzing the lipoprotein profile in a given mouse at a given time point with nonterminal bleeding. The method is simple to set up with commercially available parts and convenient to run.
Analytical Biochemistry 06/2008; 376(2):268-74. · 3.00 Impact Factor
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ABSTRACT: Glucocorticoid action is linked to the development of obesity and insulin resistance. Inhibition of 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been proposed as a strategy to suppress glucocorticoid action in a tissue-specific manner. A large variety of 11β-HSD1 inhibitor classes are under investigation by the pharmaceutical industry to treat type 2 diabetes and obesity.
Mini Reviews in Medicinal Chemistry 05/2008; 8(7):702-710. · 2.53 Impact Factor
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ABSTRACT: Malonyl-CoA decarboxylase (MCD) catalyzes the conversion of malonyl-CoA to acetyl-CoA and thereby regulates malonyl-CoA levels in cells. Malonyl-CoA is a potent inhibitor of mitochondrial carnitine palmitoyltransferase-1, a key enzyme involved in the mitochondrial uptake of fatty acids for oxidation. Abnormally high rates of fatty acid oxidation contribute to ischemic damage. Inhibition of MCD leads to increased malonyl-CoA and therefore decreases fatty acid oxidation, representing a novel approach for the treatment of ischemic heart injury. The commonly used MCD assay monitors the production of NADH fluorometrically, which is not ideal for library screening due to potential fluorescent interference by certain compounds. Here we report a luminescence assay for MCD activity. This assay is less susceptible to fluorescent interference by compounds. Furthermore, it is 150-fold more sensitive, with a detection limit of 20 nM acetyl-CoA, compared to 3 muM in the fluorescence assay. This assay is also amenable to automation for high-throughput screening and yields excellent assay statistics (Z' > 0.8). In addition, it can be applied to the screening for inhibitors of any other enzymes that generate acetyl-CoA.
Analytical Biochemistry 05/2008; 376(1):122-30. · 3.00 Impact Factor
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ABSTRACT: The metabolic syndrome is a group of disorders including obesity, insulin resistance, atherogenic dyslipidemia, hyperglycemia, and hypertension. To date, few animal models have been described to recapitulate the phenotypes of the syndrome. In this study, we generated and characterized two lines of triple-knockout mice that are deficient in either apolipoprotein E (Apoe(-/-)) or low-density lipoprotein receptor (Ldlr(-/-)) and express no leptin (Lep(ob/ob)) or apolipoprotein B-48 but exclusively apolipoprotein B-100 (Apob(100/100)). These two lines are referred to as Apoe triple-knockout-Apoe 3KO (Apoe(-/-)Apob(100/100)Lep(ob/ob)) and Ldlr triple-knockout-Ldlr 3KO (Ldlr(-/-)Apob(100/100)Lep(ob/ob)) mice. Both lines develop obesity, hyperinsulinemia, hyperlipidemia, hypertension, and atherosclerosis. However, only Apoe 3KO mice are hyperglycemic and glucose intolerant and are more obese than Ldlr 3KO mice. To evaluate the utility of these lines as pharmacological models, we treated both with leptin and found that leptin therapy ameliorated most metabolic derangements. Leptin was more effective in improving glucose tolerance in Ldlr 3KO than Apoe 3KO animals. The reduction of plasma cholesterol by leptin in Ldlr 3KO mice can be accounted for by its suppressive effect on food intake. However, in Apoe 3KO mice, leptin further reduced plasma cholesterol independently of its effect on food intake, and this improvement correlated with a smaller plaque lesion area. These effects suggest a direct role of leptin in modulating VLDL levels and, likewise, the lesion areas in VLDL-enriched animals. These two lines of mice represent new models with features of the metabolic syndrome and will be useful in testing therapies targeted for combating the human condition.
AJP Endocrinology and Metabolism 04/2008; 294(3):E496-505. · 4.75 Impact Factor
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ABSTRACT: 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is the enzyme that converts cortisone to cortisol. A growing body of evidence suggests that selective inhibition of 11beta-HSD1 could potentially treat the metabolic syndrome. This review provides an overview of compounds reported to have in vivo inhibitory activity against this enzyme. A major focus of this review is Amgen's 11beta-HSD1 program which includes a variety of in vivo data for a lead compound from our thiazolone class of inhibitors. Finally, an update on the current known clinical data is discussed.
Current topics in medicinal chemistry 02/2008; 8(17):1508-23. · 4.47 Impact Factor
