Guocheng Huang, Aeran Jung, Li-Xuan Li, Nayeon Do, Sungwon Jung, Yubum Jeon, Dongxu Zuo, Minh Thanh La, Nguyen Van Manh, Peter M Blumberg, Hongryul Yoon, Yoonji Lee, Jihyae Ann, Jeewoo Lee
A series of 1,4-benzoxazin-3-one analogs were investigated to discover mode-selective TRPV1 antagonists, since such antagonists are predicted to minimize target-based adverse effects. Using the high-affinity antagonist 2 as the lead structure, the structure activity relationship was studied by modifying the A-region through incorporation of a polar side chain on the benzoxazine and then by changing the C-region with a variety of substituted pyridine, pyrazole and thiazole moieties. The t-butyl pyrazole and thiazole C-region analogs provided high potency as well as mode-selectivity...
April 6, 2024: Bioorganic & Medicinal Chemistry Letters