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N-杂芳基烷基取代-2-(2-呋喃基)噻唑并[5,4-d]嘧啶-5,7-二胺类衍生物作为人 A 腺苷受体反向激动剂的构效关系研究及药理学特性

Structure-activity relationship studies and pharmacological characterization of N-heteroarylalkyl-substituted-2-(2-furanyl)thiazolo[5,4-d]pyrimidine-5,7-diamine-based derivatives as inverse agonists at human A adenosine receptor.

机构信息

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy.

Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy.

出版信息

Eur J Med Chem. 2018 Jul 15;155:552-561. doi: 10.1016/j.ejmech.2018.06.020. Epub 2018 Jun 9.

DOI:10.1016/j.ejmech.2018.06.020
PMID:29909340
Abstract

This paper describes the synthesis and characterization of N-(hetero)arylalkyl-substituted-thiazolo [5,4-d]pyrimidine-5,7-diamine derivatives (4-19) as novel human (h) A adenosine receptor (AR) inverse agonists. Competition binding and cyclic AMP assays indicate that the examined compounds behave as hA AR inverse agonists showing binding affinity values in the nanomolar or subnanomolar range. Notably, compounds 4, 5, 6 and 11 showed two affinity values for the hA ARs with the highest (KH) falling in the femtomolar range and the lowest (KL) of the nanomolar order. In addition, in cyclic AMP assays, compounds 4, 5, 6 and 11 exhibited potency (IC) values in the picomolar range. This study has confirmed that 2-(2-furanyl)thiazolo [5,4-d]pyrimidine-5,7-diamine-based derivatives represent a unique new class of hA AR inverse agonists.

摘要

本文描述了 N-（杂芳基）烷基取代的噻唑并[5,4-d]嘧啶-5,7-二胺衍生物（4-19）的合成与表征，这些化合物是新型人（h）A 腺苷受体（AR）反向激动剂。竞争结合和环 AMP 测定表明，所研究的化合物表现为 hA AR 反向激动剂，其结合亲和力值在纳摩尔或亚纳摩尔范围内。值得注意的是，化合物 4、5、6 和 11 对 hA AR 表现出两种亲和力值，其中最高（KH）值在飞摩尔范围内，最低（KL）值在纳摩尔范围内。此外，在环 AMP 测定中，化合物 4、5、6 和 11 表现出皮摩尔范围内的效力（IC）值。本研究证实，2-（2-呋喃基）噻唑并[5,4-d]嘧啶-5,7-二胺基衍生物代表了一类独特的新型 hA AR 反向激动剂。

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