SAR studies around a series of triazolopyridines as potent and selective PI3Kγ inhibitors

Bioorg Med Chem Lett. 2012 Aug 15;22(16):5257-63. doi: 10.1016/j.bmcl.2012.06.049. Epub 2012 Jun 23.


Herein we describe the SAR of a novel series of 6-aryl-2-amino-triazolopyridines as potent and selective PI3Kγ inhibitors. The 6-aryl-triazolopyridine core was identified by chemoproteomic screening of a kinase focused library. Rapid chemical expansion around a bi-functional core identified the key features required for PI3Kγ activity and selectivity. The series was optimized to afford 43 (CZC19945), a potent PI3Kγ inhibitor with high oral bioavailability and selectivity over PI3Kα and PI3Kδ. Modification to the core afforded 53 (CZC24832) which showed increased selectivity over the entire kinome in particular over PI3Kβ.

MeSH terms

  • Administration, Oral
  • Animals
  • Arthritis / drug therapy
  • Binding Sites
  • Cell Line, Tumor
  • Class Ib Phosphatidylinositol 3-Kinase / metabolism
  • Computer Simulation
  • Disease Models, Animal
  • Half-Life
  • Humans
  • Mice
  • Microsomes / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use
  • Rats
  • Structure-Activity Relationship


  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Isoforms
  • Pyridines
  • Class Ib Phosphatidylinositol 3-Kinase