Synthesis and optimization of 4,5,6,7-tetrahydrooxazolo[4,5-c] pyridines as potent and orally-active metabotropic glutamate receptor 5 negative allosteric modulators

被引：1

作者：

Hirose, Wataru ^{[1
]}

Kato, Yoshihiro ^{[1
]}

Natsutani, Itaru ^{[2
]}

Takata, Makoto ^{[1
]}

Kitaichi, Maiko ^{[1
]}

Imai, Satoki ^{[2
]}

Hayashi, Shun ^{[2
]}

Arai, Yukiyo ^{[1
]}

Hoshino, Kohei ^{[1
]}

Yoshida, Kohzo ^{[1
]}

机构：

[1] Sumitomo Dainippon Pharma, Drug Res Div, Konohana Ku, 3-1-98 Kasugade Naka, Osaka 5540022, Japan

[2] Sumitomo Dainippon Pharma, Drug Res Div, 33-94 Enoki Cho, Suita, Osaka 5640053, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 18期

关键词：

mGluR5; Negative allosteric modulator; CNS drug discovery; Anti-depressant agent; CLINICAL DEVELOPMENT; INHIBITORS; MGLU(5); PHARMACOLOGY; DESIGN; MPEP;

D O I：

10.1016/j.bmcl.2017.08.030

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We describe here the design, synthesis and characterization of a series of 4,5,6,7-tetrahydrooxazolo[4,5-c] pyridines as metabotropic glutamate receptor (mGluR) 5 negative allosteric modulators (NAMs). Optimization of the substituents led to the identification of several compounds with good pharmacokinetic profiles, including long half life and high oral bioavailability, in both rats and monkeys. The receptor occupancy test in the rat cortex revealed favorable brain penetration of these compounds. The reprsentative compound 13 produced oral antidepressant-like effect in the rat forced swimming test (MED: 0.3 mg/kg, q.d.). (c) 2017 Elsevier Ltd. All rights reserved.

引用

页码：4331 / 4335

页数：5

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