2. Academic Validation
  3. Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease

  • J Med Chem. 2015 Sep 24;58(18):7381-99. doi: 10.1021/acs.jmedchem.5b00767.
Kenneth Down 1 2 3,  Augustin Amour 1 2 3,  Ian R Baldwin 1 2 3,  Anthony W J Cooper 1 2 3,  Angela M Deakin 1 2 3,  Leigh M Felton 1 2 3,  Stephen B Guntrip 1 2 3,  Charlotte Hardy 1 2 3,  Zoë A Harrison 1 2 3,  Katherine L Jones 1 2 3,  Paul Jones 1 2 3,  Suzanne E Keeling 1 2 3,  Joelle Le 1 2 3,  Stefano Livia 1 2 3,  Fiona Lucas 1 2 3,  Christopher J Lunniss 1 2 3,  Nigel J Parr 1 2 3,  Ed Robinson 1 2 3,  Paul Rowland 1 2 3,  Sarah Smith 1 2 3,  Daniel A Thomas 1 2 3,  Giovanni Vitulli 1 2 3,  Yoshiaki Washio 1 2 3,  J Nicole Hamblin 1 2 3
Affiliations

Affiliations

  • 1 Refractory Respiratory Inflammation DPU, and ‡Allergic Inflammation DPU, Respiratory Therapeutic Area, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
  • 2 Molecular Discovery Research, ∥Biological Sciences, and ⊥Computational Chemistry, Platform Technology & Science, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
  • 3 Experimental Medicine Unit, and ∇Epinova DPU, ImmunoInflammation Therapeutic Area, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
PMID: 26301626 DOI: 10.1021/acs.jmedchem.5b00767
Abstract

Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.

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