Synthesis and activities of imidazolyl derivatives as novel farnesyltransferase inhibitors

MEDI 83

Yeelana Shen, yeelana.shen@ipsen.com1, Philip G. Kasprzyk1, Gregoire Prevost, gregoire.prevost@ipsen.com2, and Jesse Z. Dong1. (1) IPSEN-Biomeasure Incorporated, 27 Maple Street, Milford, MA 01757-3650, (2) Ipsen-SCRAS IHB, 5 Avenue Canada, Les Ulis, France
Ras proteins play an important role in cell growth and oncogenesis. Inhibition of ras oncoprotein farnesylation is an attractive target for development of antineoplastic agents. In an effort to develop new farnesyltransferase inhibitors, we designed and studied a series of imidazolyl derivatives. The representative compound,(+/-)-1-methylsulfonyl-3-(3-chlorophenyl)-5-[amino(4-chlorophenyl) (1-methyl-1H-imidazol-5-yl)methyl]indole (compound A), exhibited an IC50 of 46.2 nM against FPTase. In tumor cell proliferation assays, an IC50 of 4.3 µM was obtained against the human pancreatic tumor cell line, MIA PaCa-2. An IC50 of 8.3 µM against the human androgen insensitive prostate cell line, DU 145, was observed. The design, synthesis and biological activities of these compounds will be described.

 

General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006