Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors

Kirk L. Stevens; Michael J. Reno; Jennifer B. Alberti; Daniel J. Price; Laurie S. Kane-Carson; Victoria B. Knick; Lisa M. Shewchuk; Anne M. Hassell; James M. Veal; Stephen T. Davis; Robert J. Griffin; Michael R. Peel

doi:10.1016/j.bmcl.2008.09.069

Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors

Kirk L. Stevens, Michael J. Reno, Jennifer B. Alberti, Daniel J. Price, Laurie S. Kane-Carson, Victoria B. Knick, Lisa M. Shewchuk, Anne M. Hassell, James M. Veal, Stephen T. Davis, Robert J. Griffin, Michael R. Peel

Cooperative Programs for the Advancement of Earth System Science

GlaxoSmithKline

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34 Scopus citations

Abstract

A novel series of pyrazolo[1,5-b]pyridazines have been synthesized and identified as cyclin dependant kinase inhibitors potentially useful for the treatment of solid tumors. Modification of the hinge-binding amine or the C(2)- and C(6)-substitutions on the pyrazolopyridazine core provided potent inhibitors of CDK4 and demonstrated enzyme selectivity against VEGFR-2 and GSK3β.

Original language	English
Pages (from-to)	5758-5762
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	21
DOIs	https://doi.org/10.1016/j.bmcl.2008.09.069
State	Published - Nov 1 2008

Keywords

CDK2
CDK4
Cancer
Cyclin-dependant kinase inhibitor
GSK3β
Pyrazolo[1,5-b] pyridazine
VEGFR-2

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10.1016/j.bmcl.2008.09.069

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Stevens, K. L., Reno, M. J., Alberti, J. B., Price, D. J., Kane-Carson, L. S., Knick, V. B., Shewchuk, L. M., Hassell, A. M., Veal, J. M., Davis, S. T., Griffin, R. J., & Peel, M. R. (2008). Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors. Bioorganic and Medicinal Chemistry Letters, 18(21), 5758-5762. https://doi.org/10.1016/j.bmcl.2008.09.069

@article{72f4265a12ec4d39a6cbaf572aeab16f,

title = "Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors",

abstract = "A novel series of pyrazolo[1,5-b]pyridazines have been synthesized and identified as cyclin dependant kinase inhibitors potentially useful for the treatment of solid tumors. Modification of the hinge-binding amine or the C(2)- and C(6)-substitutions on the pyrazolopyridazine core provided potent inhibitors of CDK4 and demonstrated enzyme selectivity against VEGFR-2 and GSK3β.",

keywords = "CDK2, CDK4, Cancer, Cyclin-dependant kinase inhibitor, GSK3β, Pyrazolo[1,5-b] pyridazine, VEGFR-2",

author = "Stevens, \{Kirk L.\} and Reno, \{Michael J.\} and Alberti, \{Jennifer B.\} and Price, \{Daniel J.\} and Kane-Carson, \{Laurie S.\} and Knick, \{Victoria B.\} and Shewchuk, \{Lisa M.\} and Hassell, \{Anne M.\} and Veal, \{James M.\} and Davis, \{Stephen T.\} and Griffin, \{Robert J.\} and Peel, \{Michael R.\}",

year = "2008",

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doi = "10.1016/j.bmcl.2008.09.069",

language = "English",

volume = "18",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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Stevens, KL, Reno, MJ, Alberti, JB, Price, DJ, Kane-Carson, LS, Knick, VB, Shewchuk, LM, Hassell, AM, Veal, JM, Davis, ST, Griffin, RJ & Peel, MR 2008, 'Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 21, pp. 5758-5762. https://doi.org/10.1016/j.bmcl.2008.09.069

TY - JOUR

T1 - Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors

AU - Stevens, Kirk L.

AU - Reno, Michael J.

AU - Alberti, Jennifer B.

AU - Price, Daniel J.

AU - Kane-Carson, Laurie S.

AU - Knick, Victoria B.

AU - Shewchuk, Lisa M.

AU - Hassell, Anne M.

AU - Veal, James M.

AU - Davis, Stephen T.

AU - Griffin, Robert J.

AU - Peel, Michael R.

PY - 2008/11/1

Y1 - 2008/11/1

N2 - A novel series of pyrazolo[1,5-b]pyridazines have been synthesized and identified as cyclin dependant kinase inhibitors potentially useful for the treatment of solid tumors. Modification of the hinge-binding amine or the C(2)- and C(6)-substitutions on the pyrazolopyridazine core provided potent inhibitors of CDK4 and demonstrated enzyme selectivity against VEGFR-2 and GSK3β.

AB - A novel series of pyrazolo[1,5-b]pyridazines have been synthesized and identified as cyclin dependant kinase inhibitors potentially useful for the treatment of solid tumors. Modification of the hinge-binding amine or the C(2)- and C(6)-substitutions on the pyrazolopyridazine core provided potent inhibitors of CDK4 and demonstrated enzyme selectivity against VEGFR-2 and GSK3β.

KW - CDK2

KW - CDK4

KW - Cancer

KW - Cyclin-dependant kinase inhibitor

KW - GSK3β

KW - Pyrazolo[1,5-b] pyridazine

KW - VEGFR-2

UR - https://www.scopus.com/pages/publications/53949085747

U2 - 10.1016/j.bmcl.2008.09.069

DO - 10.1016/j.bmcl.2008.09.069

M3 - Article

C2 - 18835709

AN - SCOPUS:53949085747

SN - 0960-894X

VL - 18

SP - 5758

EP - 5762

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 21

ER -

Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors

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