Synthetic Research Department, ASKA Pharmaceutical Co, Ltd, 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki 213-8522, Japan.
J Med Chem. 2010 Nov 11;53(21):7549-63. doi: 10.1021/jm1002292.
We have prepared a series of quinazolinone derivatives linked with piperazinylquinoline for the treatment of irritable bowel syndrome (IBS). Using pharmacophore analysis, we designed and synthesized compounds which bind to both serotonin receptor subtype 1A (5-HT(1A)) and subtype 3 (5-HT(3)). Quinazolinone derivatives with a sulfur atom in the linker showed high affinity in in vitro assays, but low in vivo activity. Focusing on the linker to improve the pharmacokinetic profile, the sulfur atom in the linker was replaced with a methylene group. Further optimization led to the discovery of compound 17m (TZB-30878) ( J. Pharmacol. Exp. Ther. 2007 , 322 , 1315 - 1323 , Patent WO2005082887 (A1), 2005 ), a novel 5-HT(1A) agonist/5-HT(3) antagonist in the 3-aminoquinazolinone series. In in vivo functional assays, 17m dose dependently inhibited the Bezold-Jarisch reflex and induced 5-HT(1A)-mediated behaviors, and in an IBS animal model, 17m significantly inhibited stress-induced defecation. Pretreatment by WAY-100635 (5-HT(1A) antagonist) significantly attenuated but did not abolish the inhibitory effects of 17m. These results suggested that 17m exerted inhibitory effects via both 5-HT(1A) agonistic and 5-HT(3) antagonistic activities and that 17m would be useful as a therapeutic agent for IBS.
我们已经制备了一系列与哌嗪基喹啉相连的喹唑啉酮衍生物，用于治疗肠易激综合征（IBS）。使用药效基团分析，我们设计并合成了与 5-羟色胺受体亚型 1A（5-HT1A）和 3（5-HT3）都结合的化合物。连接子中含有硫原子的喹唑啉酮衍生物在体外测定中显示出高亲和力，但体内活性低。为了改善药代动力学特性，我们将连接子中的硫原子替换为亚甲基。进一步的优化导致发现了化合物 17m（TZB-30878）（J. Pharmacol. Exp. Ther. 2007, 322, 1315-1323, Patent WO2005082887 (A1), 2005），这是一种新型的 3-氨基喹唑啉酮系列中的 5-HT1A 激动剂/5-HT3 拮抗剂。在体内功能测定中，17m 剂量依赖性地抑制了贝佐尔德-贾里什反射，并诱导了 5-HT1A 介导的行为，在 IBS 动物模型中，17m 显著抑制了应激诱导的排便。WAY-100635（5-HT1A 拮抗剂）预处理显著减弱但不能消除 17m 的抑制作用。这些结果表明，17m 通过 5-HT1A 激动和 5-HT3 拮抗作用发挥抑制作用，17m 将是治疗 IBS 的有用药物。
