Joel P Berger

Summary

Affiliation: Merck Research Laboratories
Country: USA

Publications

  1. ncbi PPARs: therapeutic targets for metabolic disease
    Joel P Berger
    Department of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA
    Trends Pharmacol Sci 26:244-51. 2005
  2. ncbi The mechanisms of action of PPARs
    Joel Berger
    Department of Molecular Endocrinology, Merck Research Laboratories, P O Box 2000, Rahway, New Jersey 07065, USA
    Annu Rev Med 53:409-35. 2002
  3. ncbi Peroxisome proliferator-activated receptor-gamma ligands inhibit adipocyte 11beta -hydroxysteroid dehydrogenase type 1 expression and activity
    J Berger
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    J Biol Chem 276:12629-35. 2001
  4. ncbi A PPARgamma mutant serves as a dominant negative inhibitor of PPAR signaling and is localized in the nucleus
    J Berger
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, NJ 07065, USA
    Mol Cell Endocrinol 162:57-67. 2000
  5. ncbi Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator
    Joel P Berger
    RY80N C31, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, New Jersey 07065, USA
    Mol Endocrinol 17:662-76. 2003
  6. ncbi Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects
    J Berger
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    J Biol Chem 274:6718-25. 1999
  7. ncbi A high-capacity assay for activators of glucose incorporation into glycogen in L6 muscle cells
    J Berger
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey, 07065, USA
    Anal Biochem 261:159-63. 1998
  8. ncbi Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice
    J Berger
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    Endocrinology 137:4189-95. 1996
  9. ncbi Physiological and therapeutic roles of peroxisome proliferator-activated receptors
    Joel Berger
    Department of Metabolic Disorders Diabetes, Merck Research Laboratories, PO Box 2000, Rahway, New Jersey 07065, USA
    Diabetes Technol Ther 4:163-74. 2002
  10. doi A novel selective peroxisome proliferator-activator receptor-gamma modulator-SPPARgammaM5 improves insulin sensitivity with diminished adverse cardiovascular effects
    Ching H Chang
    Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, USA
    Eur J Pharmacol 584:192-201. 2008

Collaborators

Detail Information

Publications76

  1. ncbi PPARs: therapeutic targets for metabolic disease
    Joel P Berger
    Department of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA
    Trends Pharmacol Sci 26:244-51. 2005
    ..Novel PPAR ligands are now being developed that possess broader efficacies and improved tolerability compared with currently available therapeutic agents...
  2. ncbi The mechanisms of action of PPARs
    Joel Berger
    Department of Molecular Endocrinology, Merck Research Laboratories, P O Box 2000, Rahway, New Jersey 07065, USA
    Annu Rev Med 53:409-35. 2002
    ..Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases...
  3. ncbi Peroxisome proliferator-activated receptor-gamma ligands inhibit adipocyte 11beta -hydroxysteroid dehydrogenase type 1 expression and activity
    J Berger
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    J Biol Chem 276:12629-35. 2001
    ..In sum, these data indicate that some of the beneficial effects of PPARgamma antidiabetic agents may result, at least in part, from the down-regulation of 11beta-HSD-1 expression in adipose tissue...
  4. ncbi A PPARgamma mutant serves as a dominant negative inhibitor of PPAR signaling and is localized in the nucleus
    J Berger
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, NJ 07065, USA
    Mol Cell Endocrinol 162:57-67. 2000
    ..Thus, nuclear localization of PPARgamma occurs independently of its activation state. The dominant negative mutant, hPPARgamma2Delta500, may prove useful in further studies to characterize PPAR functions both in vitro and in vivo..
  5. ncbi Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator
    Joel P Berger
    RY80N C31, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, New Jersey 07065, USA
    Mol Endocrinol 17:662-76. 2003
    ..Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome...
  6. ncbi Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects
    J Berger
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    J Biol Chem 274:6718-25. 1999
    ....
  7. ncbi A high-capacity assay for activators of glucose incorporation into glycogen in L6 muscle cells
    J Berger
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey, 07065, USA
    Anal Biochem 261:159-63. 1998
    ..We conclude that this assay should serve as a high-capacity screen to identify novel compounds that upregulate glucose anabolic metabolism in skeletal muscle. Such chemical entities may prove useful as antidiabetic agents...
  8. ncbi Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice
    J Berger
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    Endocrinology 137:4189-95. 1996
    ..Therefore, binding and transactivation assays using PPAR gamma should serve to identify other novel therapeutic agents with potential antidiabetic activities...
  9. ncbi Physiological and therapeutic roles of peroxisome proliferator-activated receptors
    Joel Berger
    Department of Metabolic Disorders Diabetes, Merck Research Laboratories, PO Box 2000, Rahway, New Jersey 07065, USA
    Diabetes Technol Ther 4:163-74. 2002
    ..This review provides an overview of the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases...
  10. doi A novel selective peroxisome proliferator-activator receptor-gamma modulator-SPPARgammaM5 improves insulin sensitivity with diminished adverse cardiovascular effects
    Ching H Chang
    Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, USA
    Eur J Pharmacol 584:192-201. 2008
    ..Thus, compounds such as SPPARgammaM5 may offer beneficial effects on glycemic control with significantly attenuated adverse effects...
  11. ncbi MK-0767, a novel dual PPARalpha/gamma agonist, displays robust antihyperglycemic and hypolipidemic activities
    Thomas W Doebber
    Department of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA
    Biochem Biophys Res Commun 318:323-8. 2004
    ..The efficacies of MK-0767 and simvastatin were additive when given together. We conclude that MK-0767 is a potent dual PPARalpha/gamma agonist with robust insulin sensitizing and hypolipidemic activities...
  12. ncbi Discovery of a novel series of peroxisome proliferator-activated receptor alpha/gamma dual agonists for the treatment of type 2 diabetes and dyslipidemia
    Kun Liu
    Merck Research Laboratories, P O Box 2000, Rahway, New Jersey 07065, USA
    J Med Chem 48:2262-5. 2005
    ..The PPARalpha activity of 4 appeared to have played a significant role in lowering glucose levels in db/db mice...
  13. ncbi (2R)-2-ethylchromane-2-carboxylic acids: discovery of novel PPARalpha/gamma dual agonists as antihyperglycemic and hypolipidemic agents
    Hiroo Koyama
    Department of Medicinal Chemistry, Merck Research Laboratories, P O Box 2000, Rahway, New Jersey 07065 0900, USA
    J Med Chem 47:3255-63. 2004
    ..Compound 48 exhibited substantial antihyperglycemic and hypolipidemic activities when orally administered in three different animal models: the db/db mouse type 2 diabetes model, a Syrian hamster lipid model, and a dog lipid model...
  14. doi Discovery of a highly potent, selective, and bioavailable soluble epoxide hydrolase inhibitor with excellent ex vivo target engagement
    Hong C Shen
    Merck Research Laboratories, Merck and Co, Inc, Rahway, NJ 07065 0900, USA
    J Med Chem 52:5009-12. 2009
    ..With minimal off-target activity and a good PK profile, the benchmark 2d exhibited remarkable in vitro and ex vivo target engagement. The eutomer entA-2d also elicited vasodilation effect in rat mesenteric artery...
  15. doi Benzimidazolones: a new class of selective peroxisome proliferator-activated receptor γ (PPARγ) modulators
    Weiguo Liu
    Merck Research Laboratories, P O Box 2000, Rahway, New Jersey 07065, United States
    J Med Chem 54:8541-54. 2011
    ..Side effects, such as fluid retention and heart weight gain associated with PPARγ full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models...
  16. ncbi 5-aryl thiazolidine-2,4-diones: discovery of PPAR dual alpha/gamma agonists as antidiabetic agents
    Ranjit C Desai
    Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065 0900, USA
    Bioorg Med Chem Lett 13:2795-8. 2003
    ..Efficacy study results of some of these analogues in the db/db mice model of type 2 diabetes showed them superior to rosiglitazone in correcting hyperglycemia and hypertriglyceridemia...
  17. ncbi Novel 2,3-dihydrobenzofuran-2-carboxylic acids: highly potent and subtype-selective PPARalpha agonists with potent hypolipidemic activity
    Guo Q Shi
    Department of Medicinal Chemistry, Merck Research Laboratories, P O Box 2000, Rahway, New Jersey 07065 0900, USA
    J Med Chem 48:5589-99. 2005
    ....
  18. doi Discovery of (2R)-2-(3-{3-[(4-Methoxyphenyl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl}phenoxy)butanoic acid (MK-0533): a novel selective peroxisome proliferator-activated receptor gamma modulator for the treatment of type 2 diabetes mellitus w
    John J Acton
    Merck Research Laboratories, Merck and Co, Inc, RY800 C114, Rahway, New Jersey 07065, USA
    J Med Chem 52:3846-54. 2009
    ..Further investigation of 6 is warranted to determine if the improvement in mechanism-based side effects observed in preclinical species will be recapitulated in humans...
  19. doi Novel transcriptome profiling analyses demonstrate that selective peroxisome proliferator-activated receptor γ (PPARγ) modulators display attenuated and selective gene regulatory activity in comparison with PPARγ full agonists
    Yejun Tan
    Department of Informatics and Analysis, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    Mol Pharmacol 82:68-79. 2012
    ....
  20. ncbi Design and synthesis of alpha-aryloxyphenylacetic acid derivatives: a novel class of PPARalpha/gamma dual agonists with potent antihyperglycemic and lipid modulating activity
    Guo Q Shi
    Departments of Medicinal Chemistry, Merck Research Laboratories, P O Box 2000, Rahway, New Jersey 07065 0900, USA
    J Med Chem 48:4457-68. 2005
    ..They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay...
  21. doi Discovery of a peroxisome proliferator activated receptor gamma (PPARgamma) modulator with balanced PPARalpha activity for the treatment of type 2 diabetes and dyslipidemia
    Weiguo Liu
    Merck Research Laboratories, Rahway, New Jersey 07065, USA
    J Med Chem 52:4443-53. 2009
    ..The moderate PPARalpha activity of 12d not only contributed to the agent's ability to manage lipid profiles but also appears to have potentiated its PPARgamma efficacy in lowering glucose levels in preclinical diabetic animal models...
  22. ncbi Peroxisome proliferator-activated receptor (PPAR)-alpha agonism prevents the onset of type 2 diabetes in Zucker diabetic fatty rats: A comparison with PPAR gamma agonism
    Raynald Bergeron
    Department of Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    Endocrinology 147:4252-62. 2006
    ..Unlike the PPAR gamma agonist, the PPAR alpha agonist demonstrated efficacy without inducing body weight gain and cardiomegaly. This study suggests a possible role for PPAR alpha agonists in the prevention of type 2 diabetes mellitus...
  23. ncbi (2R)-2-methylchromane-2-carboxylic acids: discovery of selective PPARalpha agonists as hypolipidemic agents
    Hiroo Koyama
    Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000 Rahway, NJ 07065, USA
    Bioorg Med Chem Lett 15:3347-51. 2005
    ..As a result, highly potent, and selective PPARalpha agonists were discovered. The optimized compound 43 exhibited robust lowering of total cholesterol levels in hamster and dog animal models...
  24. doi Discovery of 3,3-disubstituted piperidine-derived trisubstituted ureas as highly potent soluble epoxide hydrolase inhibitors
    Hong C Shen
    Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065 0900, USA
    Bioorg Med Chem Lett 19:5314-20. 2009
    ..This observation further challenges the premise that sEH inhibition can provide a viable approach to the treatment of hypertensive patients...
  25. ncbi Design and synthesis of potent and subtype-selective PPARalpha agonists
    Ranjit C Desai
    Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
    Bioorg Med Chem Lett 16:1673-8. 2006
    ..Based on the results of the efficacy studies in the hamster and dog models of dyslipidemia and the desired pharmacokinetic data, the optimized compound 39 was selected for further profiling...
  26. ncbi Aryloxazolidinediones: identification of potent orally active PPAR dual alpha/gamma agonists
    Ranjit C Desai
    Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
    Bioorg Med Chem Lett 13:3541-4. 2003
    ..Based on the results of efficacy studies in the db/db mice model of type 2 diabetes and the desired pharmacokinetic parameters, compound 12 was selected for further profiling...
  27. pmc Downstream signaling pathways in mouse adipose tissues following acute in vivo administration of fibroblast growth factor 21
    Eric S Muise
    Discovery and Preclinical Sciences, Merck Research Laboratories, Merck Sharp and Dohme Corp, Whitehouse Station, New Jersey, United States of America
    PLoS ONE 8:e73011. 2013
    ....
  28. pmc cSSMD: assessing collective activity for addressing off-target effects in genome-scale RNA interference screens
    Xiaohua Douglas Zhang
    Biometrics Research, Merck Research Laboratories, West Point, PA 19486, USA
    Bioinformatics 27:2775-81. 2011
    ..Off-target activity commonly exists in RNA interference (RNAi) screens and often generates false positives. Existing analytic methods for addressing the off-target effects are demonstrably inadequate in RNAi confirmatory screens...
  29. ncbi Synthesis and biological activities of novel aryl indole-2-carboxylic acid analogs as PPARgamma partial agonists
    James F Dropinski
    Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
    Bioorg Med Chem Lett 15:5035-8. 2005
    ..Compound 5 was selected for in vivo testing in the db/db mouse model of type 2 diabetes and resulted in reduction of hyperglycemia at comparable plasma exposure when compared to rosiglitazone...
  30. doi Development of a novel GLUT4 translocation assay for identifying potential novel therapeutic targets for insulin sensitization
    Franklin Liu
    Metabolic Disorders Diabetes, Merck and Co, Inc, Rahway, NJ 07065, USA
    Biochem J 418:413-20. 2009
    ..In combination with more physiologically relevant secondary assays in myotubes and adipocytes, this assay system can be used to identify potential novel therapeutic targets for the treatment of Type 2 diabetes...
  31. doi FGF21 suppresses hepatic glucose production through the activation of atypical protein kinase Cι/λ
    Ling Jie Kong
    Merck Research Laboratories, RY80T B119, Rahway, NJ 07065, USA
    Eur J Pharmacol 702:302-8. 2013
    ..Furthermore, hepatic PKCι/λ phosphorylation was upregulated in FGF21-treated diabetic db/db mice.These data support the proposition that FGF21 inhibits hepatic glucose production by the PI3K-dependent activation of PKCι/λ...
  32. ncbi O-arylmandelic acids as highly selective human PPAR alpha/gamma agonists
    Alan D Adams
    Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co Inc, PO Box 2000 Rahway, NJ 07065, USA
    Bioorg Med Chem Lett 13:3185-90. 2003
    ..These PPARalpha-weighted agonists do not show the typical PPARgamma associated side effects of BAT proliferation and cardiac hypertrophy in a rat tolerability assay...
  33. doi Design and synthesis of a new class of malonyl-CoA decarboxylase inhibitors with anti-obesity and anti-diabetic activities
    Haifeng Tang
    Department of Medicinal Chemistry, Metabolic Disorders, Drug Metabolism and Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, USA
    Bioorg Med Chem Lett 20:6088-92. 2010
    ..Key analogs caused dose-dependent decreases in food intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in elevated blood glucose in a murine model of type II diabetes...
  34. pmc Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice
    Carina P Tan
    Department of Metabolic Disorders Diabetes, Merck Research Laboratories, Rahway, New Jersey, USA
    Diabetes 57:2211-9. 2008
    ..We sought to evaluate the specific role of GPR40 in islets and its potential as a therapeutic target using compounds that specifically activate GPR40...
  35. doi Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor gamma and altered metabolic states
    Eric S Muise
    Departments of Molecular Profiling, Merck Research Laboratories, P O Box 2000, Rahway, NJ 07065, USA
    Mol Pharmacol 74:403-12. 2008
    ..These results suggest a role for FGF21 in mediating the antidiabetic activities of PPARgamma agonists...
  36. ncbi A high-capacity assay for PPARgamma ligand regulation of endogenous aP2 expression in 3T3-L1 cells
    G Marie Thompson
    Department of Metabolic Disorders, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065, USA
    Anal Biochem 330:21-8. 2004
    ..Since the assay obviates the need for RNA isolation and is performed in an automatable multiwell format, it can serve as a high-throughput, cell-based screen for the identification and characterization of PPARgamma modulators...
  37. ncbi Amphipathic 3-phenyl-7-propylbenzisoxazoles; human pPaR gamma, delta and alpha agonists
    Alan D Adams
    Departments of Basic Chemistry, Merck Research Laboratories, Merck and Co Inc, PO Box 2000, Rahway, NJ 07065, USA
    Bioorg Med Chem Lett 13:931-5. 2003
    ..Good functional receptor selectivity for PPARalpha and gamma over PPARdelta can be obtained...
  38. ncbi Peroxisome proliferator-activated receptor gamma agonists inhibit adipocyte expression of alpha1-acid glycoprotein
    Gino Castriota
    Department of Metabolic Disorders, RY80N C31, Merck Research Laboratories, 126 East Lincoln Avenue, P O Box 2000, Rahway, NJ 07065, USA
    Cell Biol Int 31:586-91. 2007
    ..These results suggest a potential novel adipocytic mechanism by which PPARgamma agonists may ameliorate T2DM-associated insulin resistance and cardiovascular disease...
  39. ncbi 5-Aryl thiazolidine-2,4-diones as selective PPARgamma agonists
    Hiroo Koyama
    Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065 0900, USA
    Bioorg Med Chem Lett 13:1801-4. 2003
    ..One such compound 28 exhibited comparable levels of glucose correction to rosiglitazone in the db/db mouse type 2 diabetes animal model...
  40. ncbi Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2
    A Elbrecht
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    Biochem Biophys Res Commun 224:431-7. 1996
    ..These results indicate that the antidiabetic effects of thiazolidinediones in humans are likely to be mediated via binding to and transactivation of PPAR gamma 1 and gamma 2...
  41. ncbi A novel peroxisome proliferator-activated receptor alpha/gamma dual agonist demonstrates favorable effects on lipid homeostasis
    Qiu Guo
    Department of Atherosclerosis, Merck Research Laboratories, Rahway, New Jersey 07065 0900, USA
    Endocrinology 145:1640-8. 2004
    ..Agents with these properties may provide favorable means for treatment of type 2 diabetes and dyslipidemia and the prevention of atherosclerotic cardiovascular disease...
  42. pmc FGF21 analogs of sustained action enabled by orthogonal biosynthesis demonstrate enhanced antidiabetic pharmacology in rodents
    James Mu
    Department of Metabolic Disease Diabetes, Merck Research Laboratories, Rahway, New Jersey, USA
    Diabetes 61:505-12. 2012
    ..PEGylation of human FGF21 at a specific and preferred site confers superior metabolic pharmacology...
  43. doi Discovery of spirocyclic secondary amine-derived tertiary ureas as highly potent, selective and bioavailable soluble epoxide hydrolase inhibitors
    Hong C Shen
    Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065 0900, USA
    Bioorg Med Chem Lett 19:3398-404. 2009
    ..This study posed the question as to whether sEH inhibition provides a robust mechanism leading to a significant antihypertensive effect...
  44. ncbi Negative regulation of peroxisome proliferator-activated receptor-gamma gene expression contributes to the antiadipogenic effects of tumor necrosis factor-alpha
    B Zhang
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    Mol Endocrinol 10:1457-66. 1996
    ..3) Reduced PPAR gamma gene expression is likely to represent an important component of the mechanism by which TNF alpha exerts its antiadipogenic effects...
  45. ncbi The differential interactions of peroxisome proliferator-activated receptor gamma ligands with Tyr473 is a physical basis for their unique biological activities
    Monica Einstein
    Department of Metabolic Disorders, Merck Research Laboratories, 126 E Lincoln Ave, Rahway, NJ 07065, USA
    Mol Pharmacol 73:62-74. 2008
    ....
  46. pmc A genome-wide siRNA screen to identify modulators of insulin sensitivity and gluconeogenesis
    Ruojing Yang
    Department of Metebolic Disorders Diabetes, Merck Research Laboratories, Rahway, New Jersey, United States of America
    PLoS ONE 7:e36384. 2012
    ..Although the interests to discover novel genes that modulate insulin sensitivity and HGP are high, it remains challenging to have a human cell based system to identify novel genes...
  47. doi Highly functionalized 7-azaindoles as selective PPAR gamma modulators
    Sheryl D Debenham
    Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
    Bioorg Med Chem Lett 18:4798-801. 2008
    ..Addition of substituents at the 6-position of the 7-azaindoles improves in vitro potency and pharmacokinetics. 7-Azaindoles have significantly improved off-target profiles compared to the parent indole series...
  48. ncbi Cloning and expression of canine glucagon receptor and its use to evaluate glucagon receptor antagonists in vitro and in vivo
    Xiaodong Yang
    Department of Metabolic Disorder Molecular Endocrinology, Merck Research Laboratories, Rahway, NJ 07065, USA
    Eur J Pharmacol 555:8-16. 2007
    ..The availability of the dog cDNA will facilitate the understanding of glucagon pharmacology and aid in the characterization of novel glucagon antagonists that may serve as anti-hyperglycemic treatment for type 2 diabetes mellitus...
  49. ncbi Localization of PPARdelta in murine central nervous system: expression in oligodendrocytes and neurons
    John W Woods
    Department of Inflammation Research, Merck Research Laboratories, Box 2000, RY80N A43, 126 East Lincoln Avenue, Rahway, NJ 07065 USA
    Brain Res 975:10-21. 2003
    ..At the cellular level, PPARdelta mRNA and protein were found to be expressed in oligodendrocytes and neurons but not astrocytes. Such results suggest a role for PPARdelta in both myelination and neuronal functioning within the CNS...
  50. ncbi PPAR ligands: potential therapies for metabolic syndrome
    Taro E Akiyama
    Merck Research Laboratories, PO Box 2000, RY80N C31, 126 East Lincoln Avenue, Rahway, NJ 07065, USA
    Curr Diab Rep 5:45-52. 2005
    ..This report focuses on the current understanding of the mechanisms of action of PPAR agents and their clinical use in the context of MS...
  51. ncbi Inhibition of adipocyte differentiation by HIV protease inhibitors
    B Zhang
    Department of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA
    J Clin Endocrinol Metab 84:4274-7. 1999
    ..Potential mechanisms for altered adipocyte function, including direct binding to PPARgamma or inhibition of PPARgamma-mediated gene transcription were effectively excluded...
  52. ncbi An antidiabetic thiazolidinedione potentiates insulin stimulation of glycogen synthase in rat adipose tissues
    J Berger
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    Endocrinology 137:1984-90. 1996
    ..As insulin stimulation of glycogen synthase remains wortmannin inhibitable in the presence of AD-5075, the effects of thiazolidinediones on insulin signal transduction may be phosphatidylinositol 3-kinase-dependent...
  53. ncbi Insulin- and mitogen-activated protein kinase-mediated phosphorylation and activation of peroxisome proliferator-activated receptor gamma
    B Zhang
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    J Biol Chem 271:31771-4. 1996
    ..2) PPARgamma is phosphorylated in vivo by insulin stimulation or activation of the MAP kinase pathway. 3) MAP kinase is an important mediator of cross-talk between insulin signal transduction pathways and PPARgamma function...
  54. ncbi L-764406 is a partial agonist of human peroxisome proliferator-activated receptor gamma. The role of Cys313 in ligand binding
    A Elbrecht
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    J Biol Chem 274:7913-22. 1999
    ..The results suggest a critical functional role for Cys313, and helix 3, in contributing to ligand binding and subsequent agonist-induced conformational changes...
  55. ncbi Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-alpha responses of macrophages to lipopolysaccharide in vitro or in vivo
    R Thieringer
    Departments of Endocrinology, Laboratory Animal Resources, Merck Research Laboratories, Rahway, NJ 07065, USA
    J Immunol 164:1046-54. 2000
    ..Comparable results were obtained with the corresponding lean mice. Our data suggest that compounds capable of activating PPARgamma in leukocytes will not be useful for the treatment of acute inflammation...
  56. ncbi Selective PPARgamma modulators with improved pharmacological profiles
    Kun Liu
    Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
    Bioorg Med Chem Lett 15:2437-40. 2005
    ..In vivo, these SPPARgammaMs result in potent glucose lowering in db/db mice and attenuate increases in heart weight and brown adipose tissue that is typically observed in rats upon treatment with PPARgamma full agonists...
  57. doi A strategy of employing aminoheterocycles as amide mimics to identify novel, potent and bioavailable soluble epoxide hydrolase inhibitors
    Hong C Shen
    Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065 0900, USA
    Bioorg Med Chem Lett 19:5716-21. 2009
    ..The strategy of employing aminoheterocycles as amide replacements may represent a general approach to develop mimics of known hydrolase or protease inhibitors containing an amide moiety...
  58. doi The use of SSMD-based false discovery and false nondiscovery rates in genome-scale RNAi screens
    Xiaohua Douglas Zhang
    Biometrics Research, Merck Research Laboratories, West Point, PA 19486, USA
    J Biomol Screen 15:1123-31. 2010
    ..Furthermore, the SSMD-based method results in reasonably low FDR and FNDR for selecting inhibition or activation hits. This method works effectively and should have a broad utility for hit selection in RNAi screens with replicates...
  59. ncbi Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor gamma in vascular smooth muscle cells
    Dennis Bruemmer
    Division of Endocrinology, Diabetes and Hypertension and The Gonda Goldschmied Diabetes Center, David Geffen School of Medicine, University of California, Los Angeles, Calif 90095, USA
    Circ Res 93:e38-47. 2003
    ..The full text of this article is available online at http://www.circresaha.org...
  60. pmc Dual roles for lipolysis and oxidation in peroxisome proliferation-activator receptor responses to electronegative low density lipoprotein
    Ouliana Ziouzenkova
    Cardiovascular Division, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachussetts 02115, USA
    J Biol Chem 278:39874-81. 2003
    ..These findings suggest LPL-mediated PPAR alpha activation as an alternative catabolic pathway that may limit inflammatory responses to LDL(-)...
  61. ncbi A non-thiazolidinedione partial peroxisome proliferator-activated receptor gamma ligand inhibits vascular smooth muscle cell growth
    Dennis Bruemmer
    Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California Los Angeles, Warren Hall, Suite 24 130, 900 Veteran Avenue, Los Angeles, CA 90095 7073, USA
    Eur J Pharmacol 466:225-34. 2003
    ....
  62. ncbi Peroxisome proliferator-activated receptor gamma inhibits expression of minichromosome maintenance proteins in vascular smooth muscle cells
    Dennis Bruemmer
    Division of Endocrinology, Diabetes and Hypertension and The Gonda Goldschmied Diabetes Center, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA
    Mol Endocrinol 17:1005-18. 2003
    ..These findings provide strong evidence that activation of PPARgamma attenuates MCM7 transcription and support the important role of this nuclear receptor in regulating vascular smooth muscle cell proliferation...
  63. ncbi PPAR-gamma activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion
    Mathieu Laplante
    Department of Anatomy and Physiology, Laval Hospital Research Center, School of Medicine, Laval University, Quebec, Canada
    Diabetes 52:291-9. 2003
    ..These depot-specific effects may be mediated by differential regulation of key metabolic genes, including LPL, 11beta-HSD-1, and UCP-1...
  64. ncbi Treatment of type 2 diabetic db/db mice with a novel PPARgamma agonist improves cardiac metabolism but not contractile function
    Andrew N Carley
    Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
    Am J Physiol Endocrinol Metab 286:E449-55. 2004
    ..Metabolic changes in COOH-treated db/db hearts are most likely indirect, secondary to changes in supply of exogenous substrates in vivo and insulin sensitization...
  65. ncbi Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity
    Utpal B Pajvani
    Department of Cell Biology, Division of Endocrinology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
    J Biol Chem 279:12152-62. 2004
    ..These observations suggest that the HMW adiponectin complex is the active form of this protein, which we directly demonstrate in vivo by its ability to depress serum glucose levels in a dose-dependent manner...
  66. pmc Retinaldehyde represses adipogenesis and diet-induced obesity
    Ouliana Ziouzenkova
    Cardiovascular Division, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Med 13:695-702. 2007
    ..In ob/ob mice, administrating Rald or a Raldh inhibitor reduced fat and increased insulin sensitivity. These results identify Rald as a distinct transcriptional regulator of the metabolic responses to a high-fat diet...
  67. ncbi Cardiac hypertrophy caused by peroxisome proliferator- activated receptor-gamma agonist treatment occurs independently of changes in myocardial insulin signaling
    Sandra Sena
    Division of Endocrinology, Metabolism and Diabetes, Program in Human Molecular Biology and Genetics, 15 North 2030 East, Salt Lake City, UT 84112, USA
    Endocrinology 148:6047-53. 2007
    ..These data indicate that cardiac hypertrophy after PPAR-gamma agonist treatment can occur in the absence of myocardial insulin signaling and is likely secondary to the hemodynamic consequences of plasma volume expansion...
  68. ncbi Asymmetric cleavage of beta-carotene yields a transcriptional repressor of retinoid X receptor and peroxisome proliferator-activated receptor responses
    Ouliana Ziouzenkova
    Cardiovascular Division, Brigham and Women s Hospital, Havard University, Boston, Massachusetts 02115, USA
    Mol Endocrinol 21:77-88. 2007
    ..These results also suggest a novel model of molecular endocrinology in which metabolism of a parent compound, beta-carotene, may alternatively activate (9-cisRA) or inhibit (apo14) specific nuclear receptor responses...
  69. doi Malonyl CoenzymeA decarboxylase regulates lipid and glucose metabolism in human skeletal muscle
    Karim Bouzakri
    Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
    Diabetes 57:1508-16. 2008
    ..We utilized RNA interference (siRNA)-based gene silencing to determine the direct role of MCD on metabolic responses in primary human skeletal muscle...
  70. ncbi Mechanisms of the depot specificity of peroxisome proliferator-activated receptor gamma action on adipose tissue metabolism
    Mathieu Laplante
    Laval Hospital Research Centre, Laval University, Quebec, QC, Canada G1V 4G5
    Diabetes 55:2771-8. 2006
    ....
  71. ncbi Activation of peroxisome proliferator-activated receptor gamma suppresses telomerase activity in vascular smooth muscle cells
    Daisuke Ogawa
    Division of Endocrinology and Molecular Medicine, University of Kentucky College of Medicine, Lexington, KY 40536 0200, USA
    Circ Res 98:e50-9. 2006
    ....
  72. ncbi A nonthiazolidinedione peroxisome proliferator-activated receptor gamma agonist reverses endothelial dysfunction in diabetic (db/db-/-) mice
    Andrew G Howarth
    Smooth Muscle Research Group, Rm 82A, HMRB, Faculty of Medicine, University of Calgary, Calgary, Alberta, CanadaT2N 4N1
    J Pharmacol Exp Ther 316:364-70. 2006
    ..In contrast, nonhyperglycemic ob/ob mice exhibited normal vasodilatory responses to acetylcholine and, consequently, COOH treatment had no effect on endothelial function...
  73. ncbi Integrated genomic and proteomic analyses of gene expression in Mammalian cells
    Qiang Tian
    The Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103, USA
    Mol Cell Proteomics 3:960-9. 2004
    ....
  74. ncbi Peroxisome proliferator-activated receptor gamma agonism increases the capacity for sympathetically mediated thermogenesis in lean and ob/ob mice
    Henrike Sell
    Department of Anatomy and Physiology, School of Medicine, Laval University, Quebec, Canada G1K 7P4
    Endocrinology 145:3925-34. 2004
    ..This enhanced capacity leads to increased thermogenesis under beta-adrenergic stimulation, suggesting that the sympathetic drive is blunted by PPARgamma agonism...
  75. ncbi International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors
    Liliane Michalik
    Center for Integrative Genomics, National Research Centre Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland
    Pharmacol Rev 58:726-41. 2006
    ..Thus, selective action of PPARs in vivo results from the interplay at a given time point between expression levels of each of the three PPAR and RXR isotypes, affinity for a specific promoter PPRE, and ligand and cofactor availabilities...
  76. pmc Inhibition of cardiac lipoprotein utilization by transgenic overexpression of Angptl4 in the heart
    Xinxin Yu
    Department of Physiology, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 102:1767-72. 2005
    ..This mouse model will be useful to elucidate the role of reduced fatty acid supply in the pathogenesis of heart failure and related disorders...