Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
Bioorg Med Chem Lett. 2012 Mar 15;22(6):2151-3. doi: 10.1016/j.bmcl.2012.01.139. Epub 2012 Feb 8.
A novel class of 1'-cyclobutyl-6-(4-piperidyloxy)spiro[benzopyran-2,4'-piperidine] derivatives with low nanomolar affinity for the human and rat histamine-3 receptors (H(3)Rs) are described. The spirobenzopyran piperidine ether analogs demonstrated excellent H(3)R affinity and selectivity against histamine receptor subtypes (H(1)R, H(2)R, and H(4)R), were stable in liver microsomes, and had selectivity against CYP P450 enzymes. Compounds 10, 13, 15, and 16 demonstrated high H(3)R affinity, in vitro liver microsomal stability, selectivity against CYP isoforms, moreover, these ether analogs exhibited acceptable iv pharmacokinetic (PK) properties but had poor oral exposure in rat.
一类新型的 1'-环丁基-6-(4-哌啶基氧基)螺[苯并吡喃-2,4'-哌啶]衍生物，对人和大鼠组胺-3 受体（H（3）R）具有低纳摩尔亲和力。螺苯并吡喃哌啶醚类似物表现出优异的 H（3）R 亲和力和选择性，对抗组胺受体亚型（H（1）R、H（2）R 和 H（4）R），在肝微粒体中稳定，对 CYP P450 酶具有选择性。化合物 10、13、15 和 16 表现出高的 H（3）R 亲和力、体外肝微粒体稳定性、对 CYP 同工酶的选择性，此外，这些醚类似物表现出可接受的 iv 药代动力学（PK）性质，但在大鼠中口服暴露不佳。
