2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 2. Reduction of hERG activity, observed species selectivity, and structure-activity relationships
| Autor: | Stacy Markison, Sandra M. Lechner, John Saunders, John P. Williams, Silvia Gual, Siobhan Malany, Jaimie K. Rueter, Maria Prat, Raymond S. Gross, Julio C. Castro-Palomino, Tanya Joswig, Kayvon Jalali, Zhiyang Zuo, Manisha Moorjani, Deborah H. Slee, Jose-Luis Diaz, Robert E. Petroski, María I. Crespo, Chun Yang, Yang Sai, Emily Lin, Zhihong O’Brien, Marion Lanier, Xiaohu Zhang, Jenny Wen, Mark Santos, Yongsheng Chen |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Stereochemistry medicine.drug_class hERG Drug Evaluation Preclinical Carboxamide Adenosine A1 Receptor Antagonists Chemical synthesis Adenosine A1 receptor Structure-Activity Relationship Species Specificity Drug Discovery Acetamides medicine Moiety Animals Humans Rats Wistar Receptor biology Molecular Structure Chemistry Antagonist Stereoisomerism Ether-A-Go-Go Potassium Channels Adenosine A2 Receptor Antagonists Rats Pyrimidines biology.protein Hepatocytes Microsomes Liver Molecular Medicine Selectivity |
| Zdroj: | Journal of medicinal chemistry. 51(6) |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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