Novel pyrazolo[1,5-a]pyridines with improved aqueous solubility as p110α-selective PI3 kinase inhibitors

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

doi:10.1016/j.bmcl.2016.11.078

Novel pyrazolo[1,5-a]pyridines with improved aqueous solubility as p110α-selective PI3 kinase inhibitors

Bioorg Med Chem Lett. 2017 Jan 15;27(2):187-190. doi: 10.1016/j.bmcl.2016.11.078. Epub 2016 Nov 25.

Authors

Jackie D Kendall¹, Anna C Giddens², Kit Yee Tsang², Elaine S Marshall², Claire L Lill³, Woo-Jeong Lee³, Sharada Kolekar³, Mindy Chao³, Alisha Malik³, Shuqiao Yu³, Claire Chaussade⁴, Christina Buchanan⁴, Stephen M F Jamieson⁵, Gordon W Rewcastle⁵, Bruce C Baguley⁵, William A Denny⁵, Peter R Shepherd⁴

Affiliations

¹ Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: j.kendall@auckland.ac.nz.
² Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
³ Department of Molecular Medicine and Pathology, School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
⁴ Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Department of Molecular Medicine and Pathology, School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
⁵ Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

PMID: 27923617
DOI: 10.1016/j.bmcl.2016.11.078

Abstract

As part of our investigation into pyrazolo[1,5-a]pyridines as novel p110α selective PI3 kinase inhibitors, we report a range of analogues with improved aqueous solubility by the addition of a basic amine. The compounds demonstrated comparable p110α potency and selectivity to earlier compounds but with up to 1000× greater aqueous solubility, as the hydrochloride salts. The compounds also displayed good activity in a cellular assay of PI3 kinase activity.

Keywords: Aqueous solubility; P110α; PI3 kinase; PI3K; Pyrazolo[1,5-a]pyridine; Sulfonohydrazide.

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation / drug effects
Humans
Hydrazones / chemical synthesis
Hydrazones / pharmacology
Hydrazones / toxicity
Mice
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / toxicity
Pyrazoles / chemical synthesis
Pyrazoles / pharmacology*
Pyrazoles / toxicity
Pyridines / chemical synthesis
Pyridines / pharmacology*
Pyridines / toxicity
Solubility

Substances

Hydrazones
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Pyrazoles
Pyridines