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: Jee Hee Suh, Eul Kgun Yum, Young Sik Cho
• Journal: Chemical & pharmaceutical bulletin (Chem Pharm Bull (Tokyo)) Vol. 63 Issue 8 Pg. 573-8 ( 2015) ISSN: 1347-5223 [Electronic] Japan
• PMID: 26040270 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amines
• Anti-Inflammatory Agents
• Lipoxygenase Inhibitors
• Oxazoles
• Arachidonic Acid
• Arachidonate 5-Lipoxygenase

Topics

• Amines (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Animals
• Anti-Inflammatory Agents (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Arachidonate 5-Lipoxygenase (metabolism)
• Arachidonic Acid
• Cell Line
• Ear (pathology)
• Edema (chemically induced, drug therapy, enzymology, pathology)
• Humans
• Inflammation (chemically induced, drug therapy, enzymology, pathology)
• Lipoxygenase Inhibitors (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Mice
• Oxazoles (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Structure-Activity Relationship