title: Synthesis and Biological Evaluation of N-Aryl-5-aryloxazol-2-amine Derivatives as 5-Lipoxygenase Inhibitors.
abstract: We describe the synthesis and biological evaluation of N-aryl-5-aryloxazol-2-amine derivatives that are able to inhibit 5-lipoxygenase (5-LOX), a key enzyme of leukotriene synthesis, for the treatment of inflammation-related diseases including asthma and rheumatoid arthritis. A novel structural moiety containing oxazole was initially identified from a chemical library using an in vitro enzymatic and cell-based assay, and its synthesized oxazole derivatives were further examined to develop a structure-activity relationship (SAR). SAR analysis demonstrated that a hydroxyl or amino group at the p-position on N-phenyl was essential for the 5-LOX-inhibitory activities of the derivatives, and that other halogen and methyl group-substituted derivatives affected the potency, positively or negatively. As a result, derivatives selected through first-round screening were further optimized using a cell-based assay and an in vivo assay to develop a potent, selective 5-LOX inhibitor. A final hit exhibited an improved efficacy in arachidonic acid-induced ear edema when applied topically but not orally. Moreover, it showed the additional advantage of sustainable antiinflammatory activity over a reference compound, zileuton. Taken together, chemical entities bearing an oxazole scaffold could be promising as therapeutic drugs for the treatment of chronic inflammatory skin disorders.
authors.affiliation: Pharmacological Research Center, Bio-organic Division, Korea Research Institute of Chemical Technology.
authors.forename: Jee Hee
authors.initials: JH
authors.lastname: Suh
authors.forename: Eul Kgun
authors.initials: EK
authors.lastname: Yum
authors.forename: Young Sik
authors.initials: YS
authors.lastname: Cho
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid; D002460:Cell Line; D004423:Ear / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000893:Anti-Inflammatory Agents; D016859:Lipoxygenase Inhibitors; D010080:Oxazoles; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase