5-Lipoxygenase-activating protein inhibitors. Part 3: 3-{3-tert-Butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM643)—A potent FLAP inhibitor suitable for topical administration

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 15; pp. 4598 - 4601
• Main Authors: Stock, Nicholas, Baccei, Christopher, Bain, Gretchen, Chapman, Charles, Correa, Lucia, Darlington, Janice, King, Christopher, Lee, Catherine, Lorrain, Daniel S., Prodanovich, Pat, Santini, Angelina, Schaab, Kevin, Evans, Jilly F., Hutchinson, John H., Prasit, Peppi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2010
• Subjects: 5-Lipoxygenase-Activating Proteins - metabolism; Administration, Topical; Animals; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - therapeutic use; FLAP; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - therapeutic use; Inhibitor; Leukotrienes; Leukotrienes - biosynthesis; Mice; Propionates - chemical synthesis; Propionates - chemistry; Propionates - therapeutic use; Rats; Skin Diseases - chemically induced; Skin Diseases - drug therapy; Leukotrienes; FLAP; Inhibitor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.06.011

Dermal application of the potent FLAP inhibitor, 6 (AM643) using a prototypical vehicle in a murine ear arachidonic acid model showed significant reduction in the concentrations of leukotrienes in mouse skin with concomitant reduction in ear swelling. AM643 (compound 6, 3-{3-tert-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid) was identified as a potential candidate for formulation as a topical agent for the treatment of skin disorders involving leukotriene production. Dermal application of 6 using a prototypical vehicle in a murine ear arachidonic acid model showed significant reduction in the concentrations of leukotrienes in mouse skin with concomitant reduction in ear swelling.