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Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1).

Li J, Kennedy LJ, Wang H, Li JJ, Walker SJ, Hong Z, O'Connor SP, Nayeem A, Camac DM, Morin PE, Sheriff S, Wang M, Harper T, Golla R, Seethala R, Harrity T, Ponticiello RP, Morgan NN, Taylor JR, Zebo R, Gordon DA, Robl JA
ACS Med Chem Lett 5 803-8 (2014)
Related entries: 4iju, 4ijw

Cited: 14 times
EuropePMC logo PMID: 25050169

Abstract

Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11β-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.

Articles - 4ijv mentioned but not cited (1)

  1. 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 (1)

  1. A concise review on hPXR ligand-recognizing residues and structure-based strategies to alleviate hPXR transactivation risk. Liu T, Beck JP, Hao J. RSC Med Chem 13 129-137 (2022)

Articles citing this publication (12)

  1. Physiologically-based pharmacokinetic modelling of a CYP2C19 substrate, BMS-823778, utilizing pharmacogenetic data. Gong J, Iacono L, Iyer RA, Humphreys WG, Zheng M. Br J Clin Pharmacol 84 1335-1345 (2018)
  2. Clinical Pharmacokinetics and the Impact of Genetic Polymorphism on a CYP2C19 Substrate, BMS-823778, in Healthy Subjects. Gong J, Hansen L, Iacono L. Drug Metab Dispos 46 316-325 (2018)
  3. Clinical significance of CYP2C19 polymorphisms on the metabolism and pharmacokinetics of 11β-hydroxysteroid dehydrogenase type-1 inhibitor BMS-823778. Cheng Y, Wang L, Iacono L, Zhang D, Chen W, Gong J, Humphreys WG, Gan J. Br J Clin Pharmacol 84 130-141 (2018)
  4. Synthesis and optimization of picolinamide derivatives as a novel class of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors. Ryu JH, Kim S, Lee JA, Han HY, Son HJ, Lee HJ, Kim YH, Kim JS, Park HG. Bioorg Med Chem Lett 25 1679-1683 (2015)
  5. Synthesis and biological evaluation of picolinamides as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Ryu JH, Kim S, Han HY, Son HJ, Lee HJ, Shin YA, Kim JS, Park HG. Bioorg Med Chem Lett 25 695-700 (2015)
  6. A validated enantioselective LC-MS/MS assay for quantification of a major chiral metabolite of an achiral 11-β-hydroxysteroid-dehydrogenase 1 inhibitor in human plasma: Application to a clinical pharmacokinetic study. Furlong MT, Ji QC, Iacono L, Dang O, Noren M, Bruce J, Aubry AF, Arnold ME. J Chromatogr B Analyt Technol Biomed Life Sci 1022 167-172 (2016)
  7. The syntheses of [(14) C]BMS-823778 for use in a human ADME clinical study and of [(13) CD3 (13) CD2 ]BMT-094817, a stable-isotope labeled standard of a newly detected human metabolite. Maxwell BD, Tran SB, Lago M, Li J, Bonacorsi SJ. J Labelled Comp Radiopharm 59 255-259 (2016)
  8. 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)
  9. The synthesis and analysis of [phenyl-14 C(U)]BMS-770767 and [13 C6 ]BMS-770767 for use in discovery biotransformation, human ADME and bioanalytical studies. Maxwell BD, Bonacorsi SJ. J Labelled Comp Radiopharm 59 657-664 (2016)
  10. Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1). Li J, Kennedy LJ, Walker SJ, Wang H, Li JJ, Hong Z, O'Connor SP, Ye XY, Chen S, Wu S, Yoon DS, Nayeem A, Camac DM, Ramamurthy V, Morin PE, Sheriff S, Wang M, Harper TW, Golla R, Seethala R, Harrity T, Ponticiello RP, Morgan NN, Taylor JR, Zebo R, Maxwell B, Moulin F, Gordon DA, Robl JA. ACS Med Chem Lett 9 1170-1174 (2018)
  11. KI-catalyzed oxidative cyclization of α-keto acids and 2-hydrazinopyridines: efficient one-pot synthesis of 1,2,4-triazolo[4,3-a]pyridines. Yang DS, Wang J, Gao P, Bai ZJ, Duan DZ, Fan MJ. RSC Adv 8 32597-32600 (2018)
  12. The syntheses of [13 C6 ] and [phenyl-14 C(U)]BMS-816336, an inhibitor of 11β-hydroxysteroid dehydrogenase type 1, for type 2 diabetes. Maxwell BD. J Labelled Comp Radiopharm 60 357-365 (2017)


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