作为A2A受体拮抗剂的2-氨基-N-嘧啶-4-基乙酰胺：2. hERG活性的降低、观察到的物种选择性及构效关系。

2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 2. Reduction of hERG activity, observed species selectivity, and structure-activity relationships.

作者信息

Slee Deborah H, Moorjani Manisha, Zhang Xiaohu, Lin Emily, Lanier Marion C, Chen Yongsheng, Rueter Jaimie K, Lechner Sandra M, Markison Stacy, Malany Siobhan, Joswig Tanya, Santos Mark, Gross Raymond S, Williams John P, Castro-Palomino Julio C, Crespo María I, Prat Maria, Gual Silvia, Díaz José-Luis, Jalali Kayvon, Sai Yang, Zuo Zhiyang, Yang Chun, Wen Jenny, O'Brien Zhihong, Petroski Robert, Saunders John

机构信息

Department of Medicinal Chemistry, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA.

出版信息

J Med Chem. 2008 Mar 27;51(6):1730-9. doi: 10.1021/jm701187w. Epub 2008 Feb 29.

DOI:10.1021/jm701187w

PMID:18307293

Abstract

Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.

摘要

此前我们曾描述过一系列具有出色水溶性的新型A2A受体拮抗剂。如随附论文中所述，这些拮抗剂首先经过优化以去除未取代的呋喃基部分，目的是避免由于未取代呋喃的存在而可能产生的潜在代谢问题。这项工作确定了一系列强效且选择性的甲基呋喃基衍生物。在此，我们描述了该系列的进一步优化，以提高效力，维持对人A2A受体相对于人A1受体的选择性，并使对hERG通道的活性最小化。此外，还报告了观察到的针对人和大鼠A2A受体的构效关系。