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Efficacious 11beta-hydroxysteroid dehydrogenase type I inhibitors in the diet-induced obesity mouse model.

Wan ZK, Chenail E, Xiang J, Li HQ, Ipek M, Bard J, Svenson K, Mansour TS, Xu X, Tian X, Suri V, Hahm S, Xing Y, Johnson CE, Li X, Qadri A, Panza D, Perreault M, Tobin JF, Saiah E
J Med Chem 52 5449-61 (2009)
Cited: 30 times
EuropePMC logo PMID: 19673466

Abstract

Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds 1 and 20 bound to human 11beta-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11beta-HSD1 inhibition may be a valid target for the treatment of diabetes.

Reviews - 3h6k mentioned but not cited (1)

  1. Crystal structures of 11β-hydroxysteroid dehydrogenase type 1 and their use in drug discovery. Thomas MP, Potter BV. Future Med Chem 3 367-390 (2011)

Articles - 3h6k mentioned but not cited (2)

  1. Protein Targets of Frankincense: A Reverse Docking Analysis of Terpenoids from Boswellia Oleo-Gum Resins. Byler KG, Setzer WN. Medicines (Basel) 5 (2018)
  2. Structural Insights and Docking Analysis of Adamantane-Linked 1,2,4-Triazole Derivatives as Potential 11β-HSD1 Inhibitors. Osman DA, Macías MA, Al-Wahaibi LH, Al-Shaalan NH, Zondagh LS, Joubert J, Garcia-Granda S, El-Emam AA. Molecules 26 5335 (2021)


Reviews citing this publication (7)

  1. 11β-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Chapman K, Holmes M, Seckl J. Physiol Rev 93 1139-1206 (2013)
  2. Synthesis, biology and clinical significance of pentacyclic triterpenes: a multi-target approach to prevention and treatment of metabolic and vascular diseases. Sheng H, Sun H. Nat Prod Rep 28 543-593 (2011)
  3. 11β-Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus. Pereira CD, Azevedo I, Monteiro R, Martins MJ. Diabetes Obes Metab 14 869-881 (2012)
  4. Will treating diabetes with 11β-HSD1 inhibitors affect the HPA axis? Harno E, White A. Trends Endocrinol Metab 21 619-627 (2010)
  5. 11β-Hydroxysteroid dehydrogenase type 1: potential therapeutic target for metabolic syndrome. Joharapurkar A, Dhanesha N, Shah G, Kharul R, Jain M. Pharmacol Rep 64 1055-1065 (2012)
  6. New perspectives on the development of antiobesity drugs. Costantino L, Barlocco D. Future Med Chem 7 315-336 (2015)
  7. Importance of Fluorine in Benzazole Compounds. Al-Harthy T, Zoghaib W, Abdel-Jalil R. Molecules 25 (2020)

Articles citing this publication (20)

  1. Glucose-dependent insulinotropic polypeptide reduces fat-specific expression and activity of 11β-hydroxysteroid dehydrogenase type 1 and inhibits release of free fatty acids. Gögebakan Ö, Andres J, Biedasek K, Mai K, Kühnen P, Krude H, Isken F, Rudovich N, Osterhoff MA, Kintscher U, Nauck M, Pfeiffer AF, Spranger J. Diabetes 61 292-300 (2012)
  2. Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole. Beck KR, Bächler M, Vuorinen A, Wagner S, Akram M, Griesser U, Temml V, Klusonova P, Yamaguchi H, Schuster D, Odermatt A. Biochem Pharmacol 130 93-103 (2017)
  3. Acute inhibition of 11beta-hydroxysteroid dehydrogenase type-1 improves memory in rodent models of cognition. Mohler EG, Browman KE, Roderwald VA, Cronin EA, Markosyan S, Scott Bitner R, Strakhova MI, Drescher KU, Hornberger W, Rohde JJ, Brune ME, Jacobson PB, Rueter LE. J Neurosci 31 5406-5413 (2011)
  4. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors still improve metabolic phenotype in male 11β-HSD1 knockout mice suggesting off-target mechanisms. Harno E, Cottrell EC, Yu A, DeSchoolmeester J, Gutierrez PM, Denn M, Swales JG, Goldberg FW, Bohlooly-Y M, Andersén H, Wild MJ, Turnbull AV, Leighton B, White A. Endocrinology 154 4580-4593 (2013)
  5. Structure-based design and synthesis of 1,3-oxazinan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase type 1. Xu Z, Tice CM, Zhao W, Cacatian S, Ye YJ, Singh SB, Lindblom P, McKeever BM, Krosky PM, Kruk BA, Berbaum J, Harrison RK, Johnson JA, Bukhtiyarov Y, Panemangalore R, Scott BB, Zhao Y, Bruno JG, Togias J, Guo J, Guo R, Carroll PJ, McGeehan GM, Zhuang L, He W, Claremon DA. J Med Chem 54 6050-6062 (2011)
  6. Spirocyclic ureas: orally bioavailable 11 beta-HSD1 inhibitors identified by computer-aided drug design. Tice CM, Zhao W, Xu Z, Cacatian ST, Simpson RD, Ye YJ, Singh SB, McKeever BM, Lindblom P, Guo J, Krosky PM, Kruk BA, Berbaum J, Harrison RK, Johnson JJ, Bukhtiyarov Y, Panemangalore R, Scott BB, Zhao Y, Bruno JG, Zhuang L, McGeehan GM, He W, Claremon DA. Bioorg Med Chem Lett 20 881-886 (2010)
  7. Synthesis and structure-activity relationship of 2-adamantylmethyl tetrazoles as potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Ye XY, Yoon D, Chen SY, Nayeem A, Golla R, Seethala R, Wang M, Harper T, Sleczka BG, Apedo A, Li YX, He B, Kirby M, Gordon DA, Robl JA. Bioorg Med Chem Lett 24 654-660 (2014)
  8. Discovery of SAR184841, a potent and long-lasting inhibitor of 11β-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D. Venier O, Pascal C, Braun A, Namane C, Mougenot P, Crespin O, Pacquet F, Mougenot C, Monseau C, Onofri B, Dadji-Faïhun R, Leger C, Ben-Hassine M, Van-Pham T, Ragot JL, Philippo C, Farjot G, Noah L, Maniani K, Boutarfa A, Nicolaï E, Guillot E, Pruniaux MP, Güssregen S, Engel C, Coutant AL, de Miguel B, Castro A. Bioorg Med Chem Lett 23 2414-2421 (2013)
  9. Pyrrolidine-pyrazole ureas as potent and selective inhibitors of 11β-hydroxysteroid-dehydrogenase type 1. Venier O, Pascal C, Braun A, Namane C, Mougenot P, Crespin O, Pacquet F, Mougenot C, Monseau C, Onofri B, Dadji-Faïhun R, Leger C, Ben-Hassine M, Van-Pham T, Ragot JL, Philippo C, Güssregen S, Engel C, Farjot G, Noah L, Maniani K, Nicolaï E. Bioorg Med Chem Lett 21 2244-2251 (2011)
  10. Substrate binding process and mechanistic functioning of type 1 11β-hydroxysteroid dehydrogenase from enhanced sampling methods. Favia AD, Masetti M, Recanatini M, Cavalli A. PLoS One 6 e25375 (2011)
  11. Identification of novel 11β-HSD1 inhibitors by combined ligand- and structure-based virtual screening. Lagos CF, Vecchiola A, Allende F, Fuentes CA, Tichauer JE, Valdivia C, Solari S, Campino C, Tapia-Castillo A, Baudrand R, Villarroel P, Cifuentes M, Owen GI, Carvajal CA, Fardella CE. Mol Cell Endocrinol 384 71-82 (2014)
  12. Synthesis and optimization of novel 4,4-disubstituted cyclohexylbenzamide derivatives as potent 11β-HSD1 inhibitors. Sun D, Wang Z, Caille S, DeGraffenreid M, Gonzalez-Lopez de Turiso F, Hungate R, Jaen JC, Jiang B, Julian LD, Kelly R, McMinn DL, Kaizerman J, Rew Y, Sudom A, Tu H, Ursu S, Walker N, Willcockson M, Yan X, Ye Q, Powers JP. Bioorg Med Chem Lett 21 405-410 (2011)
  13. Continuous inhibition of 11β-hydroxysteroid dehydrogenase type I in adipose tissue leads to tachyphylaxis in humans and rats but not in mice. Morentin Gutierrez P, Gyte A, deSchoolmeester J, Ceuppens P, Swales J, Stacey C, Eriksson JW, Sjöstrand M, Nilsson C, Leighton B. Br J Pharmacol 172 4806-4816 (2015)
  14. Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes. Wan ZK, Chenail E, Li HQ, Ipek M, Xiang J, Suri V, Hahm S, Bard J, Svenson K, Xu X, Tian X, Wang M, Li X, Johnson CE, Qadri A, Panza D, Perreault M, Mansour TS, Tobin JF, Saiah E. ACS Med Chem Lett 4 118-123 (2013)
  15. A novel highly potent and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, UI-1499. Byun SY, Shin YJ, Nam KY, Hong SP, Ahn SK. Life Sci 120 1-7 (2015)
  16. Adamantyl carboxamides and acetamides as potent human 11β-hydroxysteroid dehydrogenase type 1 inhibitors. Su X, Halem HA, Thomas MP, Moutrille C, Culler MD, Vicker N, Potter BV. Bioorg Med Chem 20 6394-6402 (2012)
  17. Molecular docking and structural analysis of cofactor-protein interaction between NAD⁺ and 11β-hydroxysteroid dehydrogenase type 2. Yamaguchi H, Akitaya T, Yu T, Kidachi Y, Kamiie K, Noshita T, Umetsu H, Ryoyama K. J Mol Model 18 1037-1048 (2012)
  18. Mouse 11β-hydroxysteroid dehydrogenase type 2 for human application: homology modeling, structural analysis and ligand-receptor interaction. Yamaguchi H, Akitaya T, Kidachi Y, Kamiie K, Noshita T, Umetsu H, Ryoyama K. Cancer Inform 10 287-295 (2011)
  19. Apparent mineralocorticoid excess caused by novel compound heterozygous mutations in HSD11B2 and characterized by early-onset hypertension and hypokalemia. Fan P, Lu YT, Yang KQ, Zhang D, Liu XY, Tian T, Luo F, Wang LP, Ma WJ, Liu YX, Zhang HM, Song L, Cai J, Lou Y, Zhou XL. Endocrine 70 607-615 (2020)
  20. Discovery of pyridyl sulfonamide 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors for the treatment of metabolic disorders. Yoon DS, Wu SC, Seethala R, Golla R, Nayeem A, Everlof JG, Gordon DA, Hamann LG, Robl JA. Bioorg Med Chem Lett 24 5045-5049 (2014)


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