2,6-diaryl-4-acylaminopyrimidines as potent and selective adenosine A2A antagonists with improved solubility and metabolic stability

被引：10

作者：

Moorjani, Manisha ^{[1
]}

Luo, Zhiyong ^{[1
]}

Lin, Emily ^{[1
]}

Vong, Binh G. ^{[1
]}

Chen, Yongsheng ^{[1
]}

Zhang, Xiaohu ^{[1
]}

Rueter, Jaimie K. ^{[1
]}

Gross, Raymond S. ^{[1
]}

Lanier, Marion C. ^{[1
]}

Tellew, John E. ^{[1
]}

Williams, John P. ^{[1
]}

Lechner, Sandra M. ^{[2
]}

Malany, Siobhan ^{[3
]}

Santos, Mark ^{[3
,4
]}

Crespo, Maria I. ^{[5
]}

Diaz, Jose-Luis ^{[5
]}

Saunders, John ^{[1
]}

Slee, Deborah H. ^{[1
]}

机构：

[1] Neurocrine Biosci, Dept Med Chem, San Diego, CA 92130 USA

[2] Neurocrine Biosci, Dept Neurosci, San Diego, CA 92130 USA

[3] Neurocrine Biosci, Dept Pharmacol, San Diego, CA 92130 USA

[4] Neurocrine Biosci, Dept Lead Discovery, San Diego, CA 92130 USA

[5] Almirall Res Ctr, E-08980 Barcelona, Spain

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 20期

关键词：

A(2A) antagonists; adenosine receptor; Parkinson's disease;

D O I：

10.1016/j.bmcl.2008.09.048

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In this report, the strategy and outcome of expanding SAR exploration to improve solubility and metabolic stability are discussed. Compound 35 exhibited excellent potency, selectivity over A(1) and improved solubility of >4 mg/mL at pH 8.0. In addition, compound 35 had good metabolic stability with a scaled intrinsic clearance of 3 mL/min/kg (HLM) and demonstrated efficacy in the haloperidol induced catalepsy model. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：5402 / 5405

页数：4

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