Development of novel pyridazinone-based adenosine receptor ligands

被引：4
|
作者：
Catarzi, Daniela [1 ]
Varano, Flavia [1 ]
Falsini, Matteo [1 ]
Varani, Katia [2 ]
Vincenzi, Fabrizio [2 ]
Pasquini, Silvia [2 ]
Dal Ben, Diego [3 ]
Colotta, Vittoria [1 ]
机构：
[1] Univ Firenze, Area Farm & Salute Bambino, Sez Farmaceut & Nutraceut, Dipartimento Neurosci,Psicol, Via Ugo Schiff 6, I-50019 Sesto Fiorentino, Italy
[2] Univ Ferrara, Sez Farmacol, Dipartimento Sci Med, Via Fossato Mortara 17-19, I-44121 Ferrara, Italy
[3] Univ Camerino, Scuola Sci Farm & Prodotti Salute, Via S Agostino 1, I-62032 Camerino, MC, Italy
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 09期
关键词：
G protein-coupled receptors; Adenosine receptor ligands; Thieno[2,3-d]pyridazin-5(4H)-ones; ADME properties; PHARMACOLOGICAL EVALUATION; ANTAGONISTS; SYNTHESIS; INTERNATIONAL UNION; A(2A) RECEPTOR; HIGHLY POTENT; DESIGN; A(3); DERIVATIVES; SCAFFOLD; CLASSIFICATION;
D O I：
10.1016/j.bmcl.2018.03.086
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
With the aim of finding new adenosine receptor (AR) ligands, a preliminary investigation focusing on the thieno[2,3-d] pyridazin-5(4H)-one scaffold was undertaken. The synthesized compounds 1-11 were evaluated for their binding at hA(1), hA(2)A and hA(3) ARs and efficacy at hA(2)B subtype in order to determine the affinity at the human adenosine receptor subtypes. Small structural changes on this scaffold highly influenced affinity; compound 5 (5-ethyl-7-(thiazol-2-yl) thieno[2,3-d] pyridazin-4(5H)-one) emerged as the best of this series. The simplicity of the synthetic process, the capability of the scaffold to be easily decorated, together with the predicted ADME properties confirm the role of these compounds as promising hits. A molecular docking investigation at the hA(1)AR crystal structure was performed to rationalize the SARs of the herein reported thienopyridazinones. (C) 2018 Elsevier Ltd. All rights reserved.
引用
收藏
页码：1484 / 1489
页数：6
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