4p38 › Citations

Novel acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor with reduced acyl glucuronide liability: the discovery of 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329).

Scott JS, deSchoolmeester J, Kilgour E, Mayers RM, Packer MJ, Hargreaves D, Gerhardt S, Ogg DJ, Rees A, Selmi N, Stocker A, Swales JG, Whittamore PR
J Med Chem 55 10136-47 (2012)
Cited: 13 times
EuropePMC logo PMID: 23088558

Abstract

Inhibition of 11β-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.

Articles - 4p38 mentioned but not cited (2)

  1. 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)
  2. 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)


Articles citing this publication (11)

  1. 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 5 803-808 (2014)
  2. Novel small molecule 11β-HSD1 inhibitor from the endophytic fungus Penicillium commune. Sun W, Chen X, Tong Q, Zhu H, He Y, Lei L, Xue Y, Yao G, Luo Z, Wang J, Li H, Zhang Y. Sci Rep 6 26418 (2016)
  3. Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction. Leiva R, Griñan-Ferré C, Seira C, Valverde E, McBride A, Binnie M, Pérez B, Luque FJ, Pallàs M, Bidon-Chanal A, Webster SP, Vázquez S. Eur J Med Chem 139 412-428 (2017)
  4. Inhibition of 11β-Hydroxysteroid dehydrogenase-1 with AZD4017 in patients with nonalcoholic steatohepatitis or nonalcoholic fatty liver disease: A randomized, double-blind, placebo-controlled, phase II study. Yadav Y, Dunagan K, Khot R, Venkatesh SK, Port J, Galderisi A, Cobelli C, Wegner C, Basu A, Carter R, Basu R. Diabetes Obes Metab 24 881-890 (2022)
  5. Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent In Vitro Antileishmanial Activity: Initial SAR and Assessment of In Vivo Activity. Thomas MG, De Rycker M, Wall RJ, Spinks D, Epemolu O, Manthri S, Norval S, Osuna-Cabello M, Patterson S, Riley J, Simeons FRC, Stojanovski L, Thomas J, Thompson S, Naylor C, Fiandor JM, Wyatt PG, Marco M, Wyllie S, Read KD, Miles TJ, Gilbert IH. J Med Chem 63 9523-9539 (2020)
  6. 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)
  7. 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)
  8. Novel 11β-HSD1 inhibitors: C-1 versus C-2 substitution and effect of the introduction of an oxygen atom in the adamantane scaffold. Leiva R, Seira C, McBride A, Binnie M, Luque FJ, Bidon-Chanal A, Webster SP, Vázquez S. Bioorg Med Chem Lett 25 4250-4253 (2015)
  9. Antihyperglycemic Potential of Spondias mangifera Fruits via Inhibition of 11β-HSD Type 1 Enzyme: In Silico and In Vivo Approach. Wahab S, Khalid M, Alqarni MH, Elagib MFA, Bahamdan GK, Foudah AI, Aljarba TM, Mohamed MS, Mohamed NS, Arif M. J Clin Med 12 2152 (2023)
  10. Design and synthesis of (R)-1-arylsulfonylpiperidine-2-carboxamides as 11β-hydroxysteroid dehydrogenase type 1 inhibitors. Xia G, Liu L, Liu H, Yu J, Xu Z, Chen Q, Ma C, Li P, Xiong B, Liu X, Shen J. ChemMedChem 8 577-581 (2013)
  11. Discovery of camphor-derived pyrazolones as 11β-hydroxysteroid dehydrogenase type 1 inhibitors. Gillespie P, Pietranico-Cole S, Myers M, Bilotta JA, Conde-Knape K, Fotouhi N, Goodnow RA, Guertin KR, Hamilton MM, Haynes NE, Liu B, Qi L, Ren Y, Scott NR, So SS, Spence C, Taub R, Thakkar K, Tilley JW, Zwingelstein C. Bioorg Med Chem Lett 24 2707-2711 (2014)


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