Discovery of novel PI3Kγ/δ inhibitors as potential agents for inflammation

Katie Ellard; Mihiro Sunose; Kathryn Bell; Nigel Ramsden; Giovanna Bergamini; Gitte Neubauer

doi:10.1016/j.bmcl.2012.05.121

Discovery of novel PI3Kγ/δ inhibitors as potential agents for inflammation

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4546-9. doi: 10.1016/j.bmcl.2012.05.121. Epub 2012 Jun 9.

Authors

Katie Ellard¹, Mihiro Sunose, Kathryn Bell, Nigel Ramsden, Giovanna Bergamini, Gitte Neubauer

Affiliation

¹ Cellzome Ltd, Chesterford Research Park, Little Chesterford CB10 1XL, UK. catherineellard@aol.com

PMID: 22738635
DOI: 10.1016/j.bmcl.2012.05.121

Abstract

Dual PI3Kγ/δ inhibitors have recently been shown to be suitable targets for inflammatory and respiratory diseases. In a recent study we described the discovery of selective PI3Kγ inhibitors based on a triazolopyridine scaffold. Herein, we describe the elaboration of this structural class into dual PI3Kγ/δ inhibitors with excellent selectivity over the other PI3K isoforms and the general kinome. Structural optimization led to the identification of two derivatives which showed significant efficacy in an acute model of lung inflammation.

MeSH terms

Drug Discovery
Inflammation / drug therapy
Models, Molecular
Molecular Structure
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors