Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma

  • J Med Chem. 2021 Jun 24;64(12):8053-8075. doi: 10.1021/acs.jmedchem.1c00434.
Matthew W D Perry  1 ,  Karin Björhall  2 ,  Peter Bold  3 ,  Mikael Brűlls  4 ,  Ulf Börjesson  5 ,  Johan Carlsson  6 ,  Hui-Fang Amy Chang  1 ,  Yunhua Chen  7 ,  Anders Eriksson  1 ,  Britt-Marie Fihn  3 ,  Rebecca Fransson  8 ,  Linda Fredlund  6 ,  Hongbin Ge  7 ,  Haijuan Huang  7 ,  Kostas Karabelas  9 ,  Eva Lamm Bergström  3 ,  Sarah Lever  1 ,  Helena Lindmark  6 ,  Mickael Mogemark  1 ,  Antonios Nikitidis  1 ,  Anna-Pia Palmgren  1 ,  Nils Pemberton  1 ,  Jens Petersen  10 ,  Mio Rodrigo Blomqvist  11 ,  Reed W Smith  1 ,  Matthew J Thomas  2 ,  Victoria Ullah  1 ,  Christian Tyrchan  1 ,  Tiiu Wennberg  2 ,  Annika Westin Eriksson  12 ,  Wenzhen Yang  7 ,  Shuchun Zhao  7 ,  Linda Öster  10
Affiliations
  • 1. Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 2. Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 3. DMPK, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 4. Early Product Development & Manufacturing, Pharmaceutical Sciences R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 5. Computational Chemistry, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 6. Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 7. Pharmaron Beijing Co., Ltd., No. 6 Taihe Road, BDA, Beijing 100176, P.R. China.
  • 8. Advanced Drug Delivery, Pharmaceutical Sciences R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 9. Projects, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 10. Structure & Biophysics, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 11. Bioscience Cough and In Vivo, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 12. Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
PMID: 34080862 DOI: 10.1021/acs.jmedchem.1c00434
Abstract

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of Allergic Asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.

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