Novel pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors: Exploring the benzenesulfonohydrazide SAR

Jackie D Kendall; Anna C Giddens; Kit Yee Tsang; Raphaël Frédérick; Elaine S Marshall; Ripudaman Singh; Claire L Lill; Woo-Jeong Lee; Sharada Kolekar; Mindy Chao; Alisha Malik; Shuqiao Yu; Claire Chaussade; Christina Buchanan; Gordon W Rewcastle; Bruce C Baguley; Jack U Flanagan; Stephen M F Jamieson; William A Denny; Peter R Shepherd

doi:10.1016/j.bmc.2011.11.031

Novel pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors: Exploring the benzenesulfonohydrazide SAR

Bioorg Med Chem. 2012 Jan 1;20(1):58-68. doi: 10.1016/j.bmc.2011.11.031. Epub 2011 Nov 25.

Affiliation

¹ Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. j.kendall@auckland.ac.nz

PMID: 22177407
DOI: 10.1016/j.bmc.2011.11.031

Abstract

Structure-activity relationship studies of the pyrazolo[1,5-a]pyridine class of PI3 kinase inhibitors show that substitution off the hydrazone nitrogen and replacement of the sulfonyl both gave a loss of p110α selectivity, with the exception of an N-hydroxyethyl analogue. Limited substitutions were tolerated around the phenyl ring; in particular the 2,5-substitution pattern was important for PI3 kinase activity. The N-hydroxyethyl compound also showed good inhibition of cell proliferation and inhibition of phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity. It had suitable pharmacokinetics for evaluation in vivo, and showed tumour growth inhibition in two human tumour cell lines in xenograft studies. This work has provided suggestions for the design of more soluble analogues.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3-Phosphoinositide-Dependent Protein Kinases
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use
Binding Sites
Cell Line, Tumor
Computer Simulation
Humans
Mice
Neoplasms / drug therapy
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Phosphorylation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / therapeutic use
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism
Pyrazoles / chemistry*
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacokinetics
Structure-Activity Relationship
Transplantation, Heterologous

Substances

Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Pyrazoles
Pyridines
3-Phosphoinositide-Dependent Protein Kinases
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
pyridine