1,3-Dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthines as potent A2B adenosine receptor antagonists: Design, synthesis, structure-affinity and structure-selectivity relationships

被引：26

作者：

Stefanachi, Angela ^{[1
]}

Nicolotti, Orazio ^{[1
]}

Leonetti, Francesco ^{[1
]}

Cellamare, Saverio ^{[1
]}

Campagna, Francesco ^{[1
]}

Isabel Loza, Maria ^{[2
]}

Manuel Brea, Jose ^{[2
]}

Mazza, Fernando ^{[3
]}

Gavuzzo, Enrico ^{[4
]}

Carotti, Angelo ^{[1
]}

机构：

[1] Univ Bari, Dipartimento Farmacochim, I-70125 Bari, Italy

[2] Univ Santiago de Compostela, Dept Farmacol, E-15782 Santiago De Compostela, Spain

[3] Univ Aquila, Dipartimento Chim Ingn Chim & Mat, I-67100 Laquila, Italy

[4] CNR, I-00016 Monterotondo, Rome, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 22期

关键词：

1,3-Dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthines; Adenosine receptor antagonists; Structure-affinity relationships; Structure-selectivity relationships; X-ray crystallography;

D O I：

10.1016/j.bmc.2008.09.067

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A number of 1,3-dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthines were prepared and evaluated as ligands of recombinant human adenosine receptors (hARs). Several 1,3-dipropyl derivatives endowed with nano-molar binding affinity at hA(2B) receptors, but poor selectivity over hA(2A), hA(1) and hA(3) AR subtypes were identified. A comparison with the corresponding 7-OH- and 7,9-unsubstituted-deazaxanthines revealed that 9-OH-9-deazaxanthines are more potent hA(2B) ligands with lower partition coefficients and higher water solubility compared to the other two congeneric classes of deazaxanthines. An optimization of the para-substituent of the 8-phenyl ring of 9-OH-9-deazaxanthines led to the discovery of compound 38, which exhibited outstanding hA(2B) affinity (Ki = 1.0 nM), good selectivity over hA(2A), hA(1) and hA(3) (selectivity indices = 100, 79 and 1290, respectively) and excellent antagonist potency in a functional assay on rat A(2B) (pA(2B) = 9.33). (C) 2008 Published by Elsevier Ltd.

引用

页码：9780 / 9789

页数：10

共 13 条

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BIOORGANIC & MEDICINAL CHEMISTRY, 2009, 17 (10) : 3618 - 3629
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BIOORGANIC & MEDICINAL CHEMISTRY, 2000, 8 (05) : 1183 - 1193
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