5-嘧啶酮苯氧基哌啶类化合物的合成及结构-活性关系研究作为有效的、选择性的组胺 H(3)受体反向激动剂。
Synthesis and structure-activity relationship of 5-pyridazin-3-one phenoxypiperidines as potent, selective histamine H(3) receptor inverse agonists.
机构信息
Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
出版信息
Bioorg Med Chem Lett. 2012 Jan 15;22(2):1073-7. doi: 10.1016/j.bmcl.2011.11.118. Epub 2011 Dec 4.
Optimization of the R(2) and R(6) positions of (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2a with constrained phenoxypiperidines led to the identification of 5-[4-(cyclobutyl-piperidin-4-yloxy)-phenyl]-6-methyl-2H-pyridazin-3-one 8b as a potent, selective histamine H(3) receptor antagonist with favorable pharmacokinetic properties. Compound 8b had an excellent safety genotoxocity profile for a CNS-active compound in the Ames and micronucleus tests, also displayed potent H(3)R antagonist activity in the brain in the rat dipsogenia model and robust wake activity in the rat EEG/EMG model.
（5-{4-[3-(R)-2-甲基吡咯烷-1-基-丙氧基]苯基}-2H-哒嗪-3-酮）2a 的 R(2)和 R(6)位与受约束的苯氧哌啶优化，导致鉴定出 5-[4-(环丁基-哌啶-4-基氧基)-苯基]-6-甲基-2H-哒嗪-3-酮 8b 作为一种有效的、选择性的组胺 H(3)受体拮抗剂，具有良好的药代动力学特性。化合物 8b 在 Ames 和微核试验中具有良好的安全性遗传毒性特征，对于中枢神经系统活性化合物来说，在大鼠诱发口渴模型中显示出很强的 H(3)R 拮抗剂活性，在大鼠 EEG/EMG 模型中显示出很强的唤醒活性。
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