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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
[show abstract]
[hide abstract]
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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Jing Xu,
David J Lloyd,
Clarence Hale,
Shanaka Stanislaus, Michelle Chen,
Glenn Sivits,
Steven Vonderfecht,
Randy Hecht,
Yue-Sheng Li,
Richard A Lindberg,
Jin-Long Chen,
Dae Young Jung,
Zhiyou Zhang,
Hwi-Jin Ko,
Jason K Kim,
Murielle M Véniant
[show abstract]
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ABSTRACT: Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF21 in energy metabolism and to provide mechanistic insights into its glucose and lipid-lowering effects in a high-fat diet-induced obesity (DIO) model.
DIO or normal lean mice were treated with vehicle or recombinant murine FGF21. Metabolic parameters including body weight, glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques.
FGF21 dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure and physical activity levels. FGF21 also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. The profound reduction of hepatic triglyceride levels was associated with FGF21 inhibition of nuclear sterol regulatory element binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF21 also dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body weight and adiposity.
FGF21 corrects multiple metabolic disorders in DIO mice and has the potential to become a powerful therapeutic to treat hepatic steatosis, obesity, and type 2 diabetes.
Diabetes 11/2008; 58(1):250-9. · 8.29 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
[show abstract]
[hide abstract]
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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Clarence Hale,
Murielle Véniant,
Zhulun Wang, Michelle Chen,
Jocelyn McCormick,
Rod Cupples,
Dean Hickman,
Xiaoshan Min,
Athena Sudom,
Haoda Xu,
Guy Matsumoto,
Christopher Fotsch,
David J St Jean,
Minghan Wang
[show abstract]
[hide abstract]
ABSTRACT: 11Beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid action and inhibition of this enzyme is a viable therapeutic strategy for the treatment of type 2 diabetes and the metabolic syndrome. Here, we report a potent and selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitor with a binding mode elucidated from the co-crystal structure with the human 11beta-hydroxysteroid dehydrogenase type 1. The inhibitor is bound to the steroid-binding pocket making contacts with the catalytic center and the solvent channel. The inhibitor binding is facilitated by two direct hydrogen bond interactions involving Tyrosine183 of the catalytic motif Tyr-X-X-X-Lys and Alanine172. In addition, the inhibitor makes many hydrophobic interactions with both the enzyme and the co-factor nicotinamide adenine dinucleotide phosphate (reduced). In lean C57BL/6 mice, the compound inhibited both the in vivo and ex vivo 11beta-hydroxysteroid dehydrogenase type 1 activities in a dose-dependent manner. The inhibitory effects correlate with the plasma compound concentrations, suggesting that there is a clear pharmacokinetic and pharmacodynamic relationship. Moreover, at the same doses used in the pharmacokinetic/pharmacodynamic studies, the inhibitor did not cause the activation of the hypothalamic-pituitary-adrenal axis in an acute mouse model, suggesting that this compound exhibits biological effects with minimal risk of activating the hypothalamic-pituitary-adrenal axis.
Chemical Biology & Drug Design 02/2008; 71(1):36-44. · 2.28 Impact Factor
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Chester Yuan,
David J St Jean,
Qingyian Liu,
Lynn Cai,
Aiwen Li,
Nianhe Han,
George Moniz,
Ben Askew,
Randall W Hungate,
Lars Johansson, [......],
Clarence Hale, Michelle Chen,
Rod Cupples,
Jiandong Zhang,
Steven Jordan,
Michael D Bartberger,
Yaxiong Sun,
Maurice Emery,
Minghan Wang,
Christopher Fotsch
[show abstract]
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ABSTRACT: A series of 2-anilinothiazolones were prepared as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-position of the thiazolone ring (compounds 2 and 3, respectively). The binding mode was determined through the X-ray co-crystal structure of the enzyme with compound 3. This compound was also approximately 70-fold selective over 11beta-HSD2 and was orally bioavailable in rat pharmacokinetic studies. However, compound 3 was >580-fold less active in the 11beta-HSD1 cell assay when tested in the presence of 3% human serum albumin.
Bioorganic & Medicinal Chemistry Letters 11/2007; 17(22):6056-61. · 2.55 Impact Factor
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Ki Won Kim,
Zhulun Wang,
James Busby,
Trace Tsuruda, Michelle Chen,
Clarence Hale,
Víctor M Castro,
Stefan Svensson,
Rebecca Nybo,
Fei Xiong,
Minghan Wang
[show abstract]
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ABSTRACT: 11beta-Hydroxysteroid dehydrogenase type 1 is a homodimer where the carboxyl terminus of one subunit covers the active site of the dimer partner. Based on the crystal structure with CHAPS, the carboxyl terminal tyrosine 280 (Y280) has been postulated to interact with the substrate/inhibitor at the binding pocket of the dimer partner. However, the co-crystal structure with carbenoxolone argues against this role. To clarify and reconcile these findings, here we report our mutagenesis data and demonstrate that Y280 is not involved in substrate binding but rather plays a selective role in inhibitor binding. The involvement of Y280 in inhibitor binding depends on the inhibitor chemical structure. While Y280 is not involved in the binding of carbenoxolone, it is critical for the binding of glycyrrhetinic acid.
FEBS Letters 04/2007; 581(5):995-9. · 3.54 Impact Factor
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Violeta Yu,
Yanyan Tudor,
Clarence Hale,
Matthew Plant,
Ki Won Kim,
Minghan Wang,
Yen Nguyen,
Tisha San Miguel, Michelle Chen,
Rebecca Nybo,
Jamie Baumgartner,
Robert J M Kurzeja,
David Powers
[show abstract]
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ABSTRACT: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the interconversion of inert glucocorticoid (cortisone) to the active glucocorticoid (cortisol) and is enriched in liver and fat tissues. Increasing evidence suggests that selective inhibition of 11beta-HSD1 may reduce the excess glucocorticoid levels that underlie the etiology of many common disorders that constitute the metabolic syndrome. Measurement of 11beta-HSD1 activity has historically involved the detection of cortisol by methods unfavorable for large-scale screening, such as high performance liquid chromatography or thin layer chromatography. Here we describe the development and validation of novel homogeneous time-resolved fluorescence resonance energy transfer (TR-FRET) and electrochemiluminescence assays for the measurement of cortisol. These non-radioactive assays were easy to perform and produced robust results with reference compound values comparable to those obtained by conventional methods. The TR-FRET assay was easily automated and was successfully employed for the high-throughput screening of a large compound library for inhibitors of purified human recombinant 11beta-HSD1.
Assay and Drug Development Technologies 03/2007; 5(1):105-15. · 1.73 Impact Factor
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David J St Jean,
Chester Yuan,
Eric A Bercot,
Rod Cupples, Michelle Chen,
Jenne Fretland,
Clarence Hale,
Randall W Hungate,
Renee Komorowski,
Murielle Veniant,
Minghan Wang,
Xiping Zhang,
Christopher Fotsch
[show abstract]
[hide abstract]
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 metabolic syndrome as well as type 2 diabetes. Through modification of our initial lead 1, we have discovered trifluoromethyl thiazolone 17. This compound had a Ki of 22 nM, possessed low in vivo clearance, and showed a 91% inhibition of adipose 11beta-HSD1 enzymatic activity in a mouse ex vivo pharmacodynamic model.
Journal of Medicinal Chemistry 03/2007; 50(3):429-32. · 5.25 Impact Factor
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Ki Won Kim,
Zhulun Wang,
James Busby,
Trace Tsuruda, Michelle Chen,
Clarence Hale,
Víctor M Castro,
Stefan Svensson,
Rebecca Nybo,
Fei Xiong,
Minghan Wang
[show abstract]
[hide abstract]
ABSTRACT: The catalytic motif (YSASK) at the active site of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is conserved across different species. The crystal structures of the human, guinea pig and mouse enzymes have been resolved to help identify the non-conserved residues at the active site. A tyrosine residue (Y177) upstream of the catalytic motif in human 11beta-HSD1 represents the largest difference at the active sites between the human and the rodent enzyme where the corresponding residue is glutamine. Although Y177 was postulated as a potential hydrogen bond donor in substrate binding in crystal structure-based modeling, no experimental evidence is available to support this notion. Here, we report that Y177 is not a hydrogen bond donor in substrate binding because removal of the hydroxyl group from its side chain by mutagenesis (Y177F) did not significantly change the Km value for cortisone. However, removal of the hydrophobic side chain by changing tyrosine to alanine (Y177A) or substitution with a hydrophilic side chain by changing tyrosine to glutamine (Y177Q) increased Km values for cortisone. These data suggest that Y177 is involved in substrate binding through its hydrophobic side chain but not by hydrogen bonding. In addition, the three mutations had little effect on the binding of the rodent substrate 11-dehydrocorticosterone, suggesting that Y177 does not confer substrate specificity. However, the same mutations reduced the affinity of the licorice derived 11beta-HSD1 inhibitor glycyrrhetinic acid by about 6- to 10-fold. Interestingly, the affinity of carbenoxolone, the hemisuccinate ester of glycyrrhetinic acid with a similar potency against the wildtype enzyme, was not drastically affected by the same mutations at Y177. These data suggest that Y177 has a unique role in inhibitor binding. Molecular modeling with glycyrrhetinic acid led to findings consistent with the experimental data and provided potential interaction mechanisms. Our data suggest that Y177 plays an important role in both substrate and inhibitor binding but it is unlikely a hydrogen bond donor for the substrate.
Biochimica et Biophysica Acta 05/2006; 1764(4):824-30. · 4.66 Impact Factor
