2-amino-N-pyrimidin-4-ylacetamides as A(2A) receptor antagonists: 2. Reduction of hERG activity, observed species selectivity, and structure-activity relationships

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...

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Published inJournal of medicinal chemistry Vol. 51; no. 6; pp. 1730 - 1739
Main Authors 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, Samos, Mark, Gross, Raymond S., Williams, John P., Castro-Palomino, Julio C., Crespo, Maria I., Prat, Maria, Gual, Silvia, Diaz, Jose-Luis, Jalali, Kayvon, Sai, Yang, Zuo, Zhiyang, Yang, Chun, Wen, Jenny, O'Brien, Zhihong, Petroski, Robert, Saunders, John
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 27.03.2008
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
DYSKINESIA
HIGH-AFFINITY
ADENOSINE
K+ CHANNEL
BLOCKADE
ISTRADEFYLLINE
DOPAMINE D-4 RECEPTOR
NEUROPROTECTION
PARKINSONS-DISEASE
LEVODOPA
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Summary: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, 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.
ISSN:0022-2623
DOI:10.1021/jm701187w