Referenced in: none

Automatically associated channels: Kv11.1

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

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

Journal, date & volume: J. Med. Chem., 2008 Mar 27 , 51, 1730-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/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.