Discovery of N-(1-(2-hydroxyethyl)quinolin-2-one)-N'-(1-phenyl-1H-pyrazol-5-yl)methyl) urea as Mode-Selective TRPV1 antagonist

Bioorg Med Chem Lett. 2024 Feb 12:129656. doi: 10.1016/j.bmcl.2024.129656. Online ahead of print.ABSTRACTTo discover mode-selective TRPV1 antagonists as thermoneutral drug candidates, the previous potent antagonist benzopyridone 2 was optimized based on the pharmacophore A- and C-regions. The structure activity relationship was investigated systematically by modifying the A-region by incorporating a polar side chain on the pyridone and then by changing the C-region with a variety of substituted pyridine and pyrazole moieties. The 3-t-butyl and 3-(1-methylcyclopropyl) pyrazole C-region analogs provided high potency as well as mode-selectivity. Among them, 51 and 54 displayed potent and capsaicin-selective antagonism with IC50 = 2.85 and 3.27 nM to capsaicin activation and 28.5 and 31.5 % inhibition at 3 µM concentration toward proton activation, respectively. The molecular modeling study of 51 with our homology model indicated that the hydroxyethyl side chain in the A-region interacted with Arg557 and Glu570, the urea B-region engaged in hydrogen bonding with Tyr511 and Thr550, respectively, and the pyrazole C-region made two hydrophobic interactions with the receptor. Optimization of antagonist 2, which has full antagonism for activators of all modes, lead to mode-selective antagonists 51 and 54. These observations will provide insight into the future development of clinical TRPV1 antagonists without target-based side effects.PMID:38355061 | DOI:10.1016/j.bmcl.2024.129656

Source: Bioorganic and Medicinal Chemistry Letters - February 14, 2024 Category: Chemistry Authors: Dongxu Zuo Mannkyu Hong Aeran Jung Sunho Lee Nayeon Do Sungwon Jung Yubum Jeon Ji Won Jeong Guocheng Huang Li-Xuan Li Peter M Blumberg Hongryul Yoon Yoonji Lee Jihyae Ann Jeewoo Lee Source Type: research