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采用分子简化方法探索人 A3 腺苷受体拮抗剂的结合模式：从三唑并喹喔啉到嘧啶骨架的关键研究

Scouting human A3 adenosine receptor antagonist binding mode using a molecular simplification approach: from triazoloquinoxaline to a pyrimidine skeleton as a key study.

作者信息

Morizzo Erika, Capelli Francesca, Lenzi Ombretta, Catarzi Daniela, Varano Flavia, Filacchioni Guido, Vincenzi Fabrizio, Varani Katia, Borea Pier Andrea, Colotta Vittoria, Moro Stefano

机构信息

Molecular Modeling Section, Dipartimento di Scienze Farmaceutiche, Università di Padova, via Marzolo 5, Padova, Italy.

出版信息

J Med Chem. 2007 Dec 27;50(26):6596-606. doi: 10.1021/jm070852a. Epub 2007 Nov 30.

DOI:10.1021/jm070852a
PMID:18047262
Abstract

The concept of molecular simplification as a drug design strategy to shorten synthetic routes, while keeping or enhancing the biological activity of the lead drug, has been applied to design new classes of human A3 adenosine receptor (AR) antagonists. Over the past decade, we have focused a part of our research on the study of AR antagonists belonging to strictly correlated classes of tricyclic compounds. One of these classes is represented by the 2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives, either 4-amino or 4-oxo-substituted, which were intensively investigated by evaluating the effect of different substituents on the 2-phenyl ring and on the 4-amino group. Using an in silico molecular simplification approach, a new series of easily synthesizable 2-amino/2-oxoquinazoline-4-carboxamido derivatives have been discovered, presenting high affinity and selectivity against human A3 AR.

摘要

分子简化作为一种药物设计策略，旨在缩短合成路线，同时保持或增强先导药物的生物活性，已被应用于设计新型人类A3腺苷受体（AR）拮抗剂。在过去十年中，我们将部分研究重点放在了对属于紧密相关的三环化合物类别的AR拮抗剂的研究上。其中一类以2-芳基-1,2,4-三唑并[4,3-a]喹喔啉-1-酮衍生物为代表，它们是4-氨基或4-氧代取代的，通过评估不同取代基对2-苯环和4-氨基的影响进行了深入研究。使用计算机辅助分子简化方法，发现了一系列易于合成的2-氨基/2-氧代喹唑啉-4-甲酰胺衍生物，它们对人类A3 AR具有高亲和力和选择性。

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