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

Research output: Contribution to journal › Article › peer-review

35 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",

month = nov,

day = "1",

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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