Smits Rogier A, Lim Herman D, Hanzer Agnes, Zuiderveld Obbe P, Guaita Elena, Adami Maristella, Coruzzi Gabriella, Leurs Rob, de Esch Iwan J P
Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Exact Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
J Med Chem. 2008 Apr 24;51(8):2457-67. doi: 10.1021/jm7014217. Epub 2008 Mar 22.
Using a previously reported flexible alignment model we have designed, synthesized, and evaluated a series of compounds at the human histamine H 4 receptor (H 4R) from which 2-(4-methyl-piperazin-1-yl)-quinoxaline ( 3) was identified as a new lead structure for H 4R ligands. Exploration of the structure-activity relationship (SAR) of this scaffold led to the identification of 6,7-dichloro 3-(4-methylpiperazin-1-yl)quinoxalin-2(1 H)-one (VUF 10214, 57) and 2-benzyl-3-(4-methyl-piperazin-1-yl)quinoxaline (VUF 10148, 20) as potent H 4R ligands with nanomolar affinities. In vivo studies in the rat reveal that compound 57 has significant anti-inflammatory properties in the carrageenan-induced paw-edema model.
我们使用先前报道的灵活比对模型，设计、合成并评估了一系列针对人组胺H4受体（H4R）的化合物，从中鉴定出2-(4-甲基-哌嗪-1-基)-喹喔啉（3）作为H4R配体的新先导结构。对该骨架的构效关系（SAR）进行探索，鉴定出6,7-二氯-3-(4-甲基哌嗪-1-基)喹喔啉-2(1H)-酮（VUF 10214，57）和2-苄基-3-(4-甲基-哌嗪-1-基)喹喔啉（VUF 10148，20）为具有纳摩尔亲和力的强效H4R配体。在大鼠体内的研究表明，化合物57在角叉菜胶诱导的爪肿胀模型中具有显著的抗炎特性。
