Johnson & Johnson Pharmaceutical Research & Development, L.L.C, 3210 Merryfield Row, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2010 Jun 1;20(11):3367-71. doi: 10.1016/j.bmcl.2010.04.017. Epub 2010 Apr 11.
The present work details the transformation of a series of human histamine H(4) agonists into potent functional antagonists. Replacement of the aminopyrrolidine diamine functionality with a 5,6-fused pyrrolopiperidine ring system led to an antagonist. The dissection of this fused diamine led to the eventual replacement with heterocycles. The incorporation of histamine as the terminal amine led to a very potent and selective histamine H(4) agonist; whereas incorporation of the constrained histamine analog, spinacamine, modulated the functional activity to give a partial agonist. In two separate series, we demonstrate that constraining the terminal amino portion modulated the spectrum of functional activity of histamine H(4) ligands.
本工作详细描述了一系列人源组胺 H(4) 激动剂向高效能功能拮抗剂的转变。将氨基吡咯烷二胺功能基团替换为 5,6-稠合吡咯哌啶环系统得到一个拮抗剂。对这个稠合二胺进行剖析，最终用杂环进行了取代。将组胺作为末端胺基引入得到一个非常强效和选择性的组胺 H(4) 激动剂；而将约束的组胺类似物，即螺旋胺，引入则调节了功能活性，得到一个部分激动剂。在两个独立的系列中，我们证明了末端氨基部分的约束调节了组胺 H(4) 配体的功能活性谱。
