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
  • 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.

Products