Discovery of pyrrolo[2,3-d]pyrimidin-4-ones as corticotropin-releasing factor 1 receptor antagonists with a carbonyl-based hydrogen bonding acceptor

被引：6

作者：

Aso, Kazuyoshi ^{[1
]}

Kobayashi, Katsumi ^{[1
]}

Mochizuki, Michiyo ^{[1
]}

Kanzaki, Naoyuki ^{[2
]}

Sako, Yuu ^{[3
]}

Yano, Takahiko ^{[3
]}

机构：

[1] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Med Chem Res Labs, Yodogawa Ku, Osaka 5328686, Japan

[2] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Discovery Res Ctr, Yodogawa Ku, Osaka 5328686, Japan

[3] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Pharmaceut Res Labs, Yodogawa Ku, Osaka 5328686, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 08期

关键词：

Corticotropin-releasing factor; CRF1; antagonist; Pyrrolo[2,3-d]pyrimidin-4-one; Hydrogen bonding acceptor; PLACEBO-CONTROLLED TRIAL; THYMIDYLATE SYNTHASE; MOLECULAR-PROPERTIES; MAJOR DEPRESSION; STRESS-RESPONSE; CRF RECEPTOR; ANXIETY; EFFICACY; LACKING; SAFETY;

D O I：

10.1016/j.bmcl.2011.02.086

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new class of pyrrolo[2,3-d]pyrimidin-4-one corticotropin-releasing factor 1 (CRF1) receptor antagonists has been designed and synthesized. In general, reported CRF1 receptor antagonists possess a sp(2)-nitrogen atom as hydrogen bonding acceptor (HBA) on their core scaffolds. We proposed to use a carbonyl group of pyrrolo[2,3-d]pyrimidin-4-one derivatives as a replacement for the sp(2)-nitrogen atom as HBA in classical CRF1 receptor antagonists. As a result, several pyrrolo[2,3-d]pyrimidin-4-one derivatives showed CRF1 receptor binding affinity with IC50 values in the submicromolar range. Ex vivo I-125-sauvagine binding studies showed that 2-(dipropylamino)-3,7-dimethyl-5-(2,4,6-trimethylphenyl)-3,7-dihydro-4H-pyrrolo [2,3-d]pyrimidin-4-one (16b) (30 mg/kg, po) was able to penetrate into the brain and inhibit radioligand binding to CRF1 receptors (frontal cortex, olfactory bulb, and pituitary) in mice. We identified pyrrolo[2,3-d] pyrimidin-4-one derivatives as the first CRF1 antagonists with a carbonyl-based HBA. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：2365 / 2371

页数：7

共 26 条

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