2. Academic Validation
  3. Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma

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

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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