Discovery of dihydroquinazolinone derivatives as potent, selective, and CNS-penetrant M1 and M4 muscarinic acetylcholine receptors agonists

被引：15

作者：

Uruno, Yoshiharu ^{[1
]}

Konishi, Yasuko ^{[1
]}

Suwa, Atsushi ^{[1
]}

Takai, Kentaro ^{[2
]}

Tojo, Kengo ^{[1
]}

Nakako, Tomokazu ^{[2
]}

Sakai, Mutsuko ^{[1
]}

Enomoto, Takeshi ^{[2
]}

Matsuda, Harumi ^{[2
]}

Kitamura, Atsushi ^{[2
]}

Sumiyoshi, Takaaki ^{[1
]}

机构：

[1] Sumitomo Dainippon Pharma Co Ltd, Drug Res Div, Konohana Ku, Osaka 5540022, Japan

[2] Sumitomo Dainippon Pharma Co Ltd, Drug Res Div, Suita, Osaka 5640053, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 22期

基金：

日本学术振兴会;

关键词：

Muscarinic acetylcholine receptors; M-1 muscarinic acetylcholine receptor; M-4 muscarinic acetylcholine receptor; Partial agonist; Antipsychotic agent; Dihydroquinazolinone derivatives; MICE LACKING; PHARMACOLOGY; XANOMELINE;

D O I：

10.1016/j.bmcl.2015.09.032

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We designed and synthesized a series of dihydroquinazolinone derivatives as selective M-1 and M-4 muscarinic acetylcholine receptors agonists. Introduction of the N-carbethoxy piperidine unit into a HTS hit compound followed by optimization of the amine linker and the carbamoyl moiety led to the identification of compound 1 as a potential candidate. The identified compound 1 showed high selectivity for M-1 and M-4 muscarinic acetylcholine receptors with M-4 partial agonistic activity. In addition, compound 1 showed good brain penetration and reversed methamphetamine-induced hyperlocomotion in rats (ED50 = 3.0 mg/kg, sc). (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：5357 / 5361

页数：5

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