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

Research output: Contribution to journalArticle

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

Fingerprint

Phosphatidylinositol 3-Kinases
Phosphorylation
Cell proliferation
Heterografts
Protein Isoforms
Cell Proliferation
pyrazolo(3,4-b)pyridine

Cite this

Kendall, J. D., O'Connor, P. D., Marshall, A. J., Frédérick, R., Marshall, E. S., Rewcastle, G. W., ... 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
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. / Discovery of pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 1. pp. 69-85.
@article{d9e0886bdd10481cba76ff3cea0efcc4,
title = "Discovery of pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors",
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.",
author = "J.D. Kendall and P.D. O'Connor and A.J. Marshall and R. Fr{\'e}d{\'e}rick and E.S. Marshall and G.W. Rewcastle and B.C. Baguley and J.U. Flanagan and S.M.F. Jamieson and W.A. Denny and C. Chaussade and C. Buchanan and P.R. Shepherd and C.L. Lill and W.-J. Lee and S. Kolekar and M. Chao and A. Malik and S. Yu",
note = "MEDLINE{\circledR} is the source for the MeSH terms of this document.",
year = "2012",
month = "1",
day = "1",
doi = "10.1016/j.bmc.2011.11.029",
language = "English",
volume = "20",
pages = "69--85",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "1",

}

Kendall, JD, O'Connor, PD, Marshall, AJ, Frédérick, R, Marshall, ES, Rewcastle, GW, Baguley, BC, Flanagan, JU, Jamieson, SMF, Denny, WA, Chaussade, C, Buchanan, C, Shepherd, PR, Lill, CL, 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, vol. 20, no. 1, pp. 69-85. https://doi.org/10.1016/j.bmc.2011.11.029

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

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 1, 01.01.2012, p. 69-85.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Discovery of pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors

AU - Kendall, J.D.

AU - O'Connor, P.D.

AU - Marshall, A.J.

AU - Frédérick, R.

AU - Marshall, E.S.

AU - Rewcastle, G.W.

AU - Baguley, B.C.

AU - Flanagan, J.U.

AU - Jamieson, S.M.F.

AU - Denny, W.A.

AU - Chaussade, C.

AU - Buchanan, C.

AU - Shepherd, P.R.

AU - Lill, C.L.

AU - Lee, W.-J.

AU - Kolekar, S.

AU - Chao, M.

AU - Malik, A.

AU - Yu, S.

N1 - MEDLINE® is the source for the MeSH terms of this document.

PY - 2012/1/1

Y1 - 2012/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84855202660&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2011.11.029

DO - 10.1016/j.bmc.2011.11.029

M3 - Article

VL - 20

SP - 69

EP - 85

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 1

ER -