Synthesis and biological profile of substituted quinolines as potent 5-Lipoxygenase inhibitors

MEDI 283

Marc Gagnon1, Christine Brideau2, Elizabeth Cauchon2, Anne Chateauneuf2, Yves Ducharme3, Richard Frenette3, Richard W. Friesen3, Sebastien Guiral2, Pierre Hamel1, Joseph A. Mancini2, Marc Ouellet2, David Percival2, Angela Styhler2, and Elizabeth Wong2. (1) Department of Medicinal Chemistry, Merck Frosst Canada & Co, 16711, Trans Canada Hwy, Kirkland, QC H9H 3L1, Canada, (2) Department of Biochemistry, Merck Frosst Canada & Co, 16711 Trans Canada Hwy, Kirkland, QC H9H 3L1, Canada, (3) Merck Frosst Canada & Co, 16711, Trans Canada Hwy, Kirkland, QC H9H 3L1, Canada
Leukotrienes are derived from the biotransformation of arachidonic acid through the action of 5-lipoxygenase and FLAP. Compounds that inhibit one of those key enzymes for the biosynthesis of leukotrienes, are postulated to be implicated in a variety of disorders including inflammatory and allergic diseases, artherosclerosis and cancer. As part of an ongoing effort, we have synthesized and evaluated a number of novel quinoline and 2-cyanoquinoline derivatives. A structure activity relationship (SAR) study led to the discovery of compounds that exhibit good to excellent in vitro activity against the human 5-LO enzyme. These compounds are also potent inhibitors of the calcium ionophore stimulated production of LTB4 in whole blood and in cell based assays. The design, the synthesis and the activity of these 5-LO inhibitors will be presented.

 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007