5-Lipoxygenase-activating protein inhibitors. Part 2: 3-{5-(( S)-1-Acetyl-2,3-dihydro-1 H-indol-2-ylmethoxy)-3- tert-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-1 H-indol-2-yl}-2,2-dimethyl-propionic acid (AM679)—A potent FLAP inhibitor

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 1; pp. 213 - 217
• Main Authors: Stock, Nicholas, Baccei, Christopher, Bain, Gretchen, Broadhead, Alex, Chapman, Charles, Darlington, Janice, King, Christopher, Lee, Catherine, Li, Yiwei, Lorrain, Daniel S., Prodanovich, Pat, Rong, Haojing, Santini, Angelina, Zunic, Jasmine, Evans, Jilly F., Hutchinson, John H., Prasit, Peppi
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 2010; Elsevier
• Subjects: 5-Lipoxygenase-Activating Proteins; Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - metabolism; FLAP; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Inhibitors; Leukotrienes; Leukotrienes - blood; Leukotrienes - metabolism; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Medical sciences; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Mice; Models, Animal; Pentanoic Acids - chemical synthesis; Pentanoic Acids - chemistry; Pentanoic Acids - pharmacology; Pharmacology. Drug treatments; Rats; Structure-Activity Relationship; FLAP; Leukotrienes; Inhibitors; Human; Nitrogen heterocycle; Antiinflammatory agent; Benzene derivatives; 5-Lipoxygenase activating protein; In vitro; Blood; Leukotriene B4; Structure activity relation; Carboxylic acid; Bicyclic compound; Pyrimidine derivatives; Aromatic compound; Inhibition; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.10.131

The SAR of a potent series of FLAP inhibitors is described culminating in the identification of lead compound 39 (AM679). A series of potent 5-lipoxygenase-activating protein (FLAP) inhibitors are herein described. SAR studies focused on the discovery of novel alicyclic moieties appended to an indole core to optimize potency, physical properties and off-target activities. Subsequent SAR on the N-benzyl substituent of the indole led to the discovery of compound 39 (AM679) which showed potent inhibition of leukotrienes in human blood and in a rodent bronchoalvelolar lavage (BAL) challenge model.