Design and synthesis of novel 2-amino-5-hydroxyindole derivatives that inhibit human 5-lipoxygenase.
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.
Landwehr
Jens
J
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.
George
Sven
S
Karg
Eva-Maria
EM
Poeckel
Daniel
D
Steinhilber
Dieter
D
Troschuetz
Reinhard
R
Werz
Oliver
O
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
D000588:Amines; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D011994:Recombinant Proteins