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Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases.

Hemmerling M, Nilsson S, Edman K, Eirefelt S, Russell W, Hendrickx R, Johnsson E, Kärrman Mårdh C, Berger M, Rehwinkel H, Abrahamsson A, Dahmén J, Eriksson AR, Gabos B, Henriksson K, Hossain N, Ivanova S, Jansson AH, Jensen TJ, Jerre A, Johansson H, Klingstedt T, Lepistö M, Lindsjö M, Mile I, Nikitidis G, Steele J, Tehler U, Wissler L, Hansson T
J Med Chem 60 8591-8605 (2017)
Cited: 14 times
EuropePMC logo PMID: 28937774

Abstract

A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.

Reviews - 5nfp mentioned but not cited (1)

  1. The Biologist's Guide to the Glucocorticoid Receptor's Structure. Deploey N, Van Moortel L, Rogatsky I, Peelman F, De Bosscher K. Cells 12 1636 (2023)

Articles - 5nfp mentioned but not cited (4)

  1. Glucocorticoid receptor complexes form cooperatively with the Hsp90 co-chaperones Pp5 and FKBPs. Kaziales A, Barkovits K, Marcus K, Richter K. Sci Rep 10 10733 (2020)
  2. Glucocorticoid resistance conferring mutation in the C-terminus of GR alters the receptor conformational dynamics. Kaziales A, Rührnößl F, Richter K. Sci Rep 11 12515 (2021)
  3. Potent Anti-Inflammatory, Arylpyrazole-Based Glucocorticoid Receptor Agonists That Do Not Impair Insulin Secretion. Kennedy BJ, Lato AM, Fisch AR, Burke SJ, Kirkland JK, Prevatte CW, Dunlap LE, Smith RT, Vogiatzis KD, Collier JJ, Campagna SR. ACS Med Chem Lett 12 1568-1577 (2021)
  4. The Synthesis and Structural Requirements for Measuring Glucocorticoid Receptor Expression In Vivo with (±)-11C-YJH08 PET. Huang Y, Zhao N, Wang YH, Truillet C, Wei J, Parker MFL, Blecha JE, Drake CR, VanBrocklin HF, Garrido-Ruiz D, Jacobson MP, Aggarwal R, Behr SC, Flavell RR, Wilson DM, Seo Y, Evans MJ. J Nucl Med 62 723-731 (2021)


Reviews citing this publication (5)

  1. Drug Concentration Asymmetry in Tissues and Plasma for Small Molecule-Related Therapeutic Modalities. Zhang D, Hop CECA, Patilea-Vrana G, Gampa G, Seneviratne HK, Unadkat JD, Kenny JR, Nagapudi K, Di L, Zhou L, Zak M, Wright MR, Bumpus NN, Zang R, Liu X, Lai Y, Khojasteh SC. Drug Metab Dispos 47 1122-1135 (2019)
  2. Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives. Zhang SG, Liang CG, Zhang WH. Molecules 23 E2783 (2018)
  3. Structural insights into glucocorticoid receptor function. Frank F, Ortlund EA, Liu X. Biochem Soc Trans 49 2333-2343 (2021)
  4. Drug design strategies for Cushing's syndrome. Usanov SA, Kliuchenovich AV, Strushkevich NV. Expert Opin Drug Discov 14 143-151 (2019)
  5. The long winding road to the safer glucocorticoid receptor (GR) targeting therapies. Lesovaya EA, Chudakova D, Baida G, Zhidkova EM, Kirsanov KI, Yakubovskaya MG, Budunova IV. Oncotarget 13 408-424 (2022)

Articles citing this publication (4)

  1. Quaternary glucocorticoid receptor structure highlights allosteric interdomain communication. Postel S, Wissler L, Johansson CA, Gunnarsson A, Gordon E, Collins B, Castaldo M, Köhler C, Öling D, Johansson P, Fröderberg Roth L, Beinsteiner B, Dainty I, Delaney S, Klaholz BP, Billas IML, Edman K. Nat Struct Mol Biol 30 286-295 (2023)
  2. Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteers. Prothon S, Wählby Hamrén U, Tehler U, Yoon E, Forsman H, Arfvidsson C, Aggarwal A, Chen Y. Drug Des Devel Ther 13 3845-3853 (2019)
  3. IM Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-2. Muñoz-Torrero D, Mangoni AA, Liu H, Hulme C, Rautio J, Karaman R, de Sousa ME, Prokai-Tatrai K, Sabatier JM, Siciliano C, Luque FJ, Kokotos G, Ragno R, Collina S, Guillou C, Gütschow M, Agrofoglio LA. Molecules 23 E65 (2017)
  4. Safety, Pharmacokinetics and Pharmacodynamics of the Selective Glucocorticoid Receptor Modulator Velsecorat (AZD7594) Following Inhalation in Healthy Volunteers. Prothon S, Aurivillius M, Tehler U, Eriksson UG, Aggarwal A, Chen Y. Drug Des Devel Ther 16 485-497 (2022)


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