期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 20, 期 1, 页码 58-68出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2011.11.031
关键词
PI3 kinase; PI3K; PIK3CA; p110 alpha; Pyrazolo[1,5-a]pyridine; Sulfonohydrazide
资金
- Health Research Council of New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery
- Pathway Therapeutics Inc
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 p110 alpha 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. (C) 2011 Elsevier Ltd. All rights reserved.
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