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
  • 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.

Products