Synthesis and Biological Evaluation of N-Aryl-5-aryloxazol-2-amine Derivatives as 5-Lipoxygenase Inhibitors

• Published in: Chemical & pharmaceutical bulletin Vol. 63; no. 8; pp. 573 - 578
• Main Authors: Suh, Jee Hee, Yum, Eul Kgun, Cho, Young Sik
• Format: Journal Article
• Language: English; Japanese
• Published: TOKYO The Pharmaceutical Society of Japan 01.08.2015; Pharmaceutical Society of Japan; Pharmaceutical Soc Japan; Japan Science and Technology Agency
• Subjects: 5-lipoxygenase; Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Amines - therapeutic use; Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; antiinflammatory activity; Arachidonate 5-Lipoxygenase - metabolism; Arachidonic Acid; Cell Line; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Ear - pathology; Edema - chemically induced; Edema - drug therapy; Edema - enzymology; Edema - pathology; Humans; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - enzymology; Inflammation - pathology; leukotriene; Life Sciences & Biomedicine; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Lipoxygenase Inhibitors - therapeutic use; Mice; oxazol-2-amine; Oxazoles - chemical synthesis; Oxazoles - chemistry; Oxazoles - pharmacology; Oxazoles - therapeutic use; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-Activity Relationship; oxazol-2-amine; POTENT; LEUKOCYTES; ZILEUTON; METABOLISM; leukotriene; LEUKOTRIENES; ASTHMA; LIVER-MICROSOMES; 5-lipoxygenase; antiinflammatory activity; INFLAMMATORY MEDIATORS
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c15-00033

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.