Download PDF
Synthesis 2010(7): 1091-1096  
DOI: 10.1055/s-0029-1219230
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

De Novo Synthesis of a Potent LIMK1 Inhibitor

Brad E. Sleebs*a,b, Ian P. Streeta,b, Xian Buc, Jonathan B. Baella,b
a The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia
b Cancer Therapeutics-CRC P/L, 4 Research Ave, La Trobe R&D Park, Bundoora, Victoria 3086, Australia
Fax: +61(3)93452129; e-Mail: sleebs@wehi.edu.au;
c SYNthesis Med Chem P/L, 528 Ruiqing Road, Heqing, Zhangjiang Modern Medical Device Park, Shanghai 201203, P. R. of China
Further Information

Publication History

Received 27 November 2009
Publication Date:
20 January 2010 (online)

    Permissions and Reprints All articles of this category

Abstract

A potent LIMK1 inhibitor, BMS4, was synthesised in six steps starting from pyrazine-2-carboximidamide, offering a significant improvement over current methods available in the literature.

Key words

kinase inhibitor - nitrogen heterocycles - pyrimidine - Suzuki coupling - cyclization

    References

  • 1 Scott RW. Olson MF. J. Mol. Med.  2007,  85:  555 
    CrossrefSearch in Google Scholar
  • 2 Wrobleski ST, Lin S, Leftheris K, He L, Seitz SP, Lin T.-A, and Vaccaro W. inventors; WO  084017.  ; Chem. Abstr. 2006, 145, 211069
  • 3 Ross-MacDonald P. de Silva H. Guo Q. Xiao H. Hung C.-Y. Penhallow B. Markwalder J. He L. Attar RM. Lin T. Seitz S. Tilford C. Wardwell-Swanson J. Jackson D. Mol. Cancer Ther.  2008,  7:  3490 
    CrossrefSearch in Google Scholar
  • 7a Littke AF. Dai C. Fu GC. J. Am. Chem. Soc.  2000,  122:  4020 
    Search in Google Scholar
  • 7b Wright SW. Hageman DL. McClure LD. J. Org. Chem.  1994,  59:  6095 
    Search in Google Scholar
  • 7c Billingsley K. Buchwald SL. J. Am. Chem. Soc.  2007,  129:  3358 
    Search in Google Scholar
  • 7d Walker SD. Barder TE. Martinelli JR. Angew. Chem. Int. Ed.  2004,  43:  1871 
    Search in Google Scholar
4

Bristol-Myers Squibb did not assign compound 1 a BMS compound number. However in the Bristol-Myers Squibb publication,³ compound 1 was referred to as ‘compound 4’. Hence, for identification purposes, we named compound 1 ‘BMS4’.

5

Communication with SYNthesis Med Chem.

6

The authors noted that the quality of Pd(PPh3)4 dramatically influences the reaction outcome.

8

Experimental details and conditions for the LIMK1 Transcreener Fluorescence Polarisation assay are available from the authors on request.