Discovery of pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors

J.D. Kendall, P.D. O'Connor, A.J. Marshall, R. Frédérick, E.S. Marshall, G.W. Rewcastle, B.C. Baguley, J.U. Flanagan, S.M.F. Jamieson, W.A. Denny, C. Chaussade, C. Buchanan, P.R. Shepherd, C.L. Lill, W.-J. Lee, S. Kolekar, M. Chao, A. Malik, S. Yu

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Abstract

We have made a novel series of pyrazolo[1,5-a]pyridines as PI3 kinase inhibitors, and demonstrated their selectivity for the p110α isoform over the other Class Ia PI3 kinases. We investigated the SAR around the pyrazolo[1,5-a]pyridine ring system, and found compound 5x to be a particularly potent example (p110α IC 0.9 nM). This compound inhibits cell proliferation and phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity, and showed in vivo activity in an HCT-116 human xenograft model.
Original languageEnglish
Pages (from-to)69-85
Number of pages17
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number1
DOIs
Publication statusPublished - 1 Jan 2012

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Kendall, J. D., O'Connor, P. D., Marshall, A. J., Frédérick, R., Marshall, E. S., Rewcastle, G. W., Baguley, B. C., Flanagan, J. U., Jamieson, S. M. F., Denny, W. A., Chaussade, C., Buchanan, C., Shepherd, P. R., Lill, C. L., Lee, W-J., Kolekar, S., Chao, M., Malik, A., & Yu, S. (2012). Discovery of pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors. Bioorganic and Medicinal Chemistry, 20(1), 69-85. https://doi.org/10.1016/j.bmc.2011.11.029