title: Design and synthesis of novel 2-amino-5-hydroxyindole derivatives that inhibit human 5-lipoxygenase.
abstract: Compounds that inhibit 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of leukotrienes (LTs), possess potential for the treatment of inflammatory and allergic diseases as well as of atherosclerosis and cancer. Here we present the design and the synthesis of a series of novel 2-amino-5-hydroxyindoles that potently inhibit isolated human recombinant 5-LO as well as 5-LO in polymorphonuclear leukocytes, exemplified by ethyl 2-[(3-chlorophenyl)amino]-5-hydroxy-1H-indole-3-carboxylate (3n, IC(50) value congruent with 300 nM). Introduction of an aryl/arylethylamino group or 4-arylpiperazin-1-yl residues into position 2 of the 5-hydroxyindoles was essential for biological activity. Whereas the 4-arylpiperazin-1-yl derivatives were more potent in cell-free assays as compared to intact cell test systems, aryl/arylethylamino derivatives inhibited 5-LO activity in intact cells and cell-free assays almost equally well. On the basis of their 5-LO inhibitory properties, these novel 2-amino-5-hydroxyindoles represent potential candidates for the pharmacological intervention with LT-associated diseases.
authors.affiliation: Department of Medicinal Chemistry, Institute for Pharmacy and Food Chemistry at the Emil-Fischer Center, Friedrich Alexander University Erlangen, Schuhstrasse 19, D-91052 Erlangen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Landwehr
authors.forename: Sven
authors.initials: S
authors.lastname: George
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Karg
authors.forename: Daniel
authors.initials: D
authors.lastname: Poeckel
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.forename: Reinhard
authors.initials: R
authors.lastname: Troschuetz
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology; D016859:Lipoxygenase Inhibitors; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D011994:Recombinant Proteins