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Optimization of brain penetrant 11β-hydroxysteroid dehydrogenase type I inhibitors and in vivo testing in diet-induced obese mice.

Goldberg FW, Dossetter AG, Scott JS, Robb GR, Boyd S, Groombridge SD, Kemmitt PD, Sjögren T, Gutierrez PM, deSchoolmeester J, Swales JG, Turnbull AV, Wild MJ
J Med Chem 57 970-86 (2014)
Cited: 11 times
EuropePMC logo PMID: 24422550

Abstract

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11β-HSD1 activity alleviates metabolic syndrome.

Articles - 4c7j mentioned but not cited (6)

  1. Crystal structure, Hirshfeld surface analysis and DFT studies of 5-(adamantan-1-yl)-3-[(4-chlorobenzyl)sulfanyl]-4-methyl-4H-1,2,4-triazole, a potential 11β-HSD1 inhibitor. Al-Wahaibi LH, Joubert J, Blacque O, Al-Shaalan NH, El-Emam AA. Sci Rep 9 19745 (2019)
  2. Novel 2-(Adamantan-1-ylamino)Thiazol-4(5H)-One Derivatives and Their Inhibitory Activity towards 11β-HSD1-Synthesis, Molecular Docking and In Vitro Studies. Studzińska R, Kupczyk D, Płaziński W, Baumgart S, Bilski R, Paprocka R, Kołodziejska R. Int J Mol Sci 22 8609 (2021)
  3. Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2. Vuorinen A, Engeli RT, Leugger S, Bachmann F, Akram M, Atanasov AG, Waltenberger B, Temml V, Stuppner H, Krenn L, Ateba SB, Njamen D, Davis RA, Odermatt A, Schuster D. J Nat Prod 80 965-974 (2017)
  4. 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)
  5. Synthesis of Novel 2-(Cyclopentylamino)thiazol-4(5H)-one Derivatives with Potential Anticancer, Antioxidant, and 11β-HSD Inhibitory Activities. Baumgart S, Kupczyk D, Archała A, Koszła O, Sołek P, Płaziński W, Płazińska A, Studzińska R. Int J Mol Sci 24 7252 (2023)
  6. Weak Noncovalent Interactions in Three Closely Related Adamantane-Linked 1,2,4-Triazole N-Mannich Bases: Insights from Energy Frameworks, Hirshfeld Surface Analysis, In Silico 11β-HSD1 Molecular Docking and ADMET Prediction. Al-Wahaibi LH, Macías MA, Blacque O, Zondagh LS, Joubert J, Thamotharan S, Percino MJ, Mohamed AAB, El-Emam AA. Molecules 27 7403 (2022)


Reviews citing this publication (2)

  1. New perspectives on the development of antiobesity drugs. Costantino L, Barlocco D. Future Med Chem 7 315-336 (2015)
  2. 11β-Hydroxysteroid Dehydrogenase Type 1 as a Potential Treatment Target in Cardiovascular Diseases. Kupczyk D, Studzińska R, Kołodziejska R, Baumgart S, Modrzejewska M, Woźniak A. J Clin Med 11 6190 (2022)

Articles citing this publication (3)

  1. Ginsenoside Rb1 increases insulin sensitivity through suppressing 11β-hydroxysteroid dehydrogenase type I. Song B, Ding L, Zhang H, Chu Y, Chang Z, Yu Y, Guo D, Zhang S, Liu X. Am J Transl Res 9 1049-1057 (2017)
  2. Discovery and Biological Evaluation of Potent and Orally Active Human 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors for the Treatment of Type 2 Diabetes Mellitus. Koike T, Shiraki R, Sasuga D, Hosaka M, Kawano T, Fukudome H, Kurosawa K, Moritomo A, Mimasu S, Ishii H, Yoshimura S. Chem Pharm Bull (Tokyo) 67 824-838 (2019)
  3. Bisphenol A Analogues Inhibit Human and Rat 11β-Hydroxysteroid Dehydrogenase 1 Depending on Its Lipophilicity. Wang H, Sang J, Ji Z, Yu Y, Wang S, Zhu Y, Li H, Wang Y, Zhu Q, Ge R. Molecules 28 4894 (2023)


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