化学
赫尔格
选择性
吡唑啉
分子模型
体内
组合化学
氢键
立体化学
磺酰
体外
代谢稳定性
分子
小分子
生物物理学
生物化学
药物化学
有机化学
钾通道
催化作用
生物技术
生物
烷基
作者
Arnold van Loevezijn,Jennifer Venhorst,Wouter Bakker,Cor G de Korte,Wouter de Looff,Stefan Verhoog,Jan-Willem van Wees,Martijn van Hoeve,Rob P. van de Woestijne,Martina A.W. van der Neut,Alice J.M. Borst,M.J.P. van Dongen,Natasja de Bruin,Hiskias G. Keizer,Chris G. Kruse
摘要
The 5-HT(6) receptor (5-HT(6)R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT(6)R antagonists to improve off-target selectivity compared to basic amine-containing scaffolds dominating the field. High-throughput screening identified the N'-(sulfonyl)pyrazoline-1-carboxamidine scaffold as a promising neutral core for starting hit-to-lead. Medicinal chemistry, molecular modeling, small molecule NMR and X-ray crystallography were subsequently applied to optimize the leads into antagonists (compounds 1-49) displaying high 5-HT(6)R affinity with optimal off-target selectivity. Unique structural features include a pseudoaromatic system and an internal hydrogen bond freezing the bioactive conformation. While physicochemical properties and CNS availability were generally favorable, significant efforts had to be made to improve metabolic stability. The optimized structure 42 is an extremely selective, hERG-free, high-affinity 5-HT(6)R antagonist showing good human in vitro metabolic stability. Rat pharmacokinetic data were sufficiently good to enable further in vivo profiling.
科研通智能强力驱动
Strongly Powered by AbleSci AI