Journal of Medicinal Chemistry p. 7381 - 7399 (2015)
Update date:2022-08-15
Topics: Selectivity Optimization Potency Indazole Inhibitor Chemical Synthesis Experimental Design Phosphoinositide 3-kinase δ (PI3Kδ) Respiratory disease
Down, Kenneth
Amour, Augustin
Baldwin, Ian R.
Cooper, Anthony W.J.
Deakin, Angela M.
Felton, Leigh M.
Guntrip, Stephen B.
Hardy, Charlotte
Harrison, Zo? A.
Jones, Katherine L.
Jones, Paul
Keeling, Suzanne E.
Le, Joelle
Livia, Stefano
Lucas, Fiona
Lunniss, Christopher J.
Parr, Nigel J.
Robinson, Ed
Rowland, Paul
Smith, Sarah
Thomas, Daniel A.
Vitulli, Giovanni
Washio, Yoshiaki
Hamblin, J. Nicole
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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