2. Academic Validation
  3. Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases

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

  • J Med Chem. 2017 Oct 26;60(20):8591-8605. doi: 10.1021/acs.jmedchem.7b01215.
Martin Hemmerling 1,  Stinabritt Nilsson 2,  Karl Edman 3,  Stefan Eirefelt 2,  Wayne Russell 2,  Ramon Hendrickx 1,  Eskil Johnsson 1,  Carina Kärrman Mårdh 1,  Markus Berger 4,  Hartmut Rehwinkel 4,  Anna Abrahamsson 1,  Jan Dahmén 2,  Anders R Eriksson 1,  Balint Gabos 2,  Krister Henriksson 2,  Nafizal Hossain 2,  Svetlana Ivanova 2,  Anne-Helene Jansson 2,  Tina J Jensen 1,  Anders Jerre 2,  Henrik Johansson 2,  Tomas Klingstedt 2,  Matti Lepistö 1,  Martin Lindsjö 5,  Irene Mile 2,  Grigorios Nikitidis 2,  John Steele 1,  Ulrika Tehler 5,  Lisa Wissler 3,  Thomas Hansson 1
Affiliations

Affiliations

  • 1 Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca , Pepparedsleden 1, Mölndal, SE 43183, Sweden.
  • 2 AstraZeneca R&D Lund , Scheelevägen 1, Lund, SE 22187, Sweden.
  • 3 Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca , Pepparedsleden 1, Mölndal, SE 43183, Sweden.
  • 4 Medicinal Chemistry Berlin, Drug Discovery, Pharmaceuticals, Bayer AG , Berlin 13353, Germany.
  • 5 Pharmaceutical Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca , Pepparedsleden 1, Mölndal, SE 43183, Sweden.
PMID: 28937774 DOI: 10.1021/acs.jmedchem.7b01215
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.

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