合成和评价吡啶酮-苯氧丙基-R-2-甲基吡咯烷类似物作为组胺 H3 受体拮抗剂。
Synthesis and evaluation of pyridone-phenoxypropyl-R-2-methylpyrrolidine analogues as histamine H3 receptor antagonists.
机构信息
Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
出版信息
Bioorg Med Chem Lett. 2011 Dec 1;21(23):7076-80. doi: 10.1016/j.bmcl.2011.09.091. Epub 2011 Sep 29.
6-{4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]-phenyl}-2H-pyridazin-3-one 6 (Irdabisant; CEP-26401) was recently reported as a potent H(3)R antagonist with excellent drug-like properties and in vivo activity that advanced into clinical evaluation. A series of pyridone analogs of 6 was synthesized and evaluated as H(3)R antagonists. Structure-activity relationships revealed that the 5-pyridone regiomer was optimal for H(3)R affinity. N-Methyl 9b showed excellent H(3)R affinity, acceptable pharmacokinetics and pharmaceutical properties. In vivo evaluation of 9b showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG model.
6-{4-[3-(R)-2-甲基吡咯烷-1-基)丙氧基]-苯基}-2H-哒嗪-3-酮 6（Irdabisant；CEP-26401）最近被报道为一种有效的 H（3）R 拮抗剂，具有优良的类药性和体内活性，已进入临床评估。合成了一系列 6 的吡啶酮类似物，并将其作为 H（3）R 拮抗剂进行了评估。构效关系研究表明，5-吡啶酮异构体对 H（3）R 亲和力最佳。N-甲基 9b 表现出优异的 H（3）R 亲和力、可接受的药代动力学和药物性质。9b 的体内评估显示，在大鼠致渴模型中具有很强的活性，在大鼠脑电图模型中具有很强的觉醒促进活性。
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