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

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

doi:10.1016/j.bmcl.2008.09.069

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

Full Record
Other Related Research

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 GSK3{beta}.

Authors:

Stevens, Kirk L; Reno, Michael J; Alberti, Jennifer B; Price, Daniel J; Kane-Carson, Laurie S; Knick, Victoria B; Shewchuk, Lisa M; Hassell, Anne M; Veal, James M; Davis, Stephen T; Griffin, Robert J; Peel, Michael R ^[1]

GSKNC

Publication Date:: Fri Oct 01 00:00:00 EDT 2010

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:: USDOE

OSTI Identifier:: 1007159

Resource Type:: Journal Article

Journal Name:: Bioorg. Med. Chem. Lett.

Additional Journal Information:: Journal Volume: 18; Journal Issue: (21) ; 11, 2008; Journal ID: ISSN 0960-894X

Country of Publication:: United States

Language:: ENGLISH

Subject:: 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; AMINES; ENZYMES; EVALUATION; MODIFICATIONS; NEOPLASMS; PHOSPHOTRANSFERASES; SYNTHESIS

Citation Formats


                    Stevens, Kirk L, Reno, Michael J, Alberti, Jennifer B, Price, Daniel J, Kane-Carson, Laurie S, Knick, Victoria B, Shewchuk, Lisa M, Hassell, Anne M, Veal, James M, Davis, Stephen T, Griffin, Robert J, and Peel, Michael R. Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors.  United States: N. p., 2010. 
        Web.  doi:10.1016/j.bmcl.2008.09.069.

Copy to clipboard


                    Stevens, Kirk L, Reno, Michael J, Alberti, Jennifer B, Price, Daniel J, Kane-Carson, Laurie S, Knick, Victoria B, Shewchuk, Lisa M, Hassell, Anne M, Veal, James M, Davis, Stephen T, Griffin, Robert J, & Peel, Michael R. Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors.  United States.  https://doi.org/10.1016/j.bmcl.2008.09.069

Copy to clipboard


                    Stevens, Kirk L, Reno, Michael J, Alberti, Jennifer B, Price, Daniel J, Kane-Carson, Laurie S, Knick, Victoria B, Shewchuk, Lisa M, Hassell, Anne M, Veal, James M, Davis, Stephen T, Griffin, Robert J, and Peel, Michael R. 2010.  
        "Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors".  United States.  https://doi.org/10.1016/j.bmcl.2008.09.069.

Copy to clipboard


                    
@article{osti_1007159,

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

  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},

  abstractNote = {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 GSK3{beta}.},

  doi          = {10.1016/j.bmcl.2008.09.069},

  url          = {https://www.osti.gov/biblio/1007159},
  journal      = {Bioorg. Med. Chem. Lett.},

  issn         = {0960-894X},

  number       = (21) ; 11, 2008,

  volume       = 18,

  place        = {United States},

  year         = {Fri Oct 01 00:00:00 EDT 2010},

  month        = {Fri Oct 01 00:00:00 EDT 2010}

}

Copy to clipboard

Journal Article:

https://doi.org/10.1016/j.bmcl.2008.09.069

Other availability

Find in Google Scholar

Search WorldCat to find libraries that may hold this journal

Save / Share:

Export Metadata

Save to My Library

Similar records in OSTI.GOV collections:

Non-hinge-binding pyrazolo[1,5-a]pyrimidines as potent B-Raf kinase inhibitors

Journal Article Berger, Dan; Torres, Nancy; Dutia, Minu; ... - Bioorg. Med. Chem. Lett.

As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class.
https://doi.org/10.1016/j.bmcl.2009.10.049
Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6-methoxyphenyl)methanone (R547), A Potent and Selective Cyclin-Dependent Kinase Inhibitor with Significiant in Vivo Antitumor Activity

Journal Article Chu, X; DePinto, W; Bartkovitz, D; ... - Journal of Medicinal Chemistry

The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitorymore »« less
https://doi.org/10.1021/jm0606138
Pyrazolo[1,5-a]pyrimidines as orally available inhibitors of cyclin-dependent kinase 2

Journal Article Paruch, Kamil; Dwyer, Michael; Alvarez, Carmen; ... - Bioorg. Med. Chem. Lett.

Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compound 15j is orally available and showed efficacy in a mouse A2780 xenograft model.
https://doi.org/10.1016/j.bmcl.2007.09.017
Crystal structure of a human cyclin-dependent kinase 6 complexwith a flavonol inhibitor, Fisetin

Journal Article Lu, Heshu; Chang, Debbie; Baratte, Blandine; ... - Journal of Medicinal Chemistry

Cyclin-dependent kinases (CDKs) play a central role in cell cycle control, apoptosis, transcription and neuronal functions. They are important targets for the design of drugs with anti-mitotic and/or anti-neurodegenerative effects. CDK4 and CDK6 form a subfamily among the CDKs in mammalian cells, as defined by sequence similarities. Compared to CDK2 and CDK5, structural information on CDK4 and CDK6 is sparse. We describe here the crystal structure of human CDK6 in complex with a viral cyclin and a flavonol inhibitor, fisetin. Fisetin binds to the active form of CDK6, forming hydrogen bonds with the side chains of residues in the bindingmore »« less
https://doi.org/10.1021/jm049353p
Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: A template-based approach-Part 2

Journal Article Labroli, Marc; Paruch, Kamil; Dwyer, Michael; ... - Bioorg. Med. Chem. Lett.

Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors.
https://doi.org/10.1016/j.bmcl.2010.10.114

Similar Records