2,6-Diaryl-4-phenacylaminopyrimidines as potent and selective adenosine A2A antagonists with reduced hERG liability

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 4, 2008, Pages 1269-1273

  Moorjani, Manisha ^a   Zhang, Xiaohu ^a   Chen, Yongsheng ^a   Lin, Emily ^a   Rueter, Jaimie K ^a   Gross, Raymond S ^a   Lanier, Marion C ^a   Tellew, John E ^a   Williams, John P ^a   Lechner, Sandra M ^b   Malany, Siobhan ^c   Santos, Mark ^c   Ekhlassi, Paddi ^a   Castro Palomino, Julio C ^d   Crespo, María I ^d   Prat, Maria ^d   Gual, Silvia ^d   Díaz, José Luis ^d   Saunders, John ^a   Slee, Deborah H ^a  

^a Neurocrine Biosciences ^*  (United States)

^b NEUROCRINE BIOSCIENCES INC   (United States)

^c Neurocrine Biosciences   (United States)

^d NONE   (Spain)

Author keywords

A2A antagonists; Adenosine receptor; hERG; Parkinson's disease; Phenacylaminopyrimidines

Indexed keywords

ADENOSINE A2A RECEPTOR ANTAGONIST; POTASSIUM CHANNEL HERG; PYRIMIDINE DERIVATIVE;

ARTICLE; DRUG MECHANISM; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; EMBRYO; HUMAN; HUMAN CELL;

CELL LINE; CYTOCHROME P-450 CYP3A; DNA-BINDING PROTEINS; DRUG DESIGN; HUMANS; KINETICS; PYRIMIDINES; RECEPTOR, ADENOSINE A2A; STRUCTURE-ACTIVITY RELATIONSHIP; TRANS-ACTIVATORS;

EID: 39049148980     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.01.036     Document Type: Article

References (17)

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11. i values were highly reproducible, the standard deviations were less than or equal to 20%. All compounds reported were assayed in 3-6 independent experiments.
12. 50 < 30 μM were assayed in two or three experiments.
13. To determine solubility of compounds, approximately 1 mg of sample was weighed into a 15-mL Falcon centrifuge tube and the weight recorded to 0.001 mg. Assay medium, (200 μL, Buffer Solution pH 2.00) was added and the sample sonicated for 10 min, then shaken overnight. The sample was then centrifuged and the supernatant was analyzed by HPLC to determine the concentration of sample in solution. The concentration in solution was then calculated based on a standard curve generated from known dilutions of authentic sample.
14. The calculated log P values stated were obtained using ACD/Labs Log P database, version 9.02 (2005), Advanced Chemistry Development Inc., Toronto, Ontario, Canada (http://www.acdlabs.com).
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16. General experimental details for this assay may be found in the following reference:. Guo Z., Zhu Y.F., Gross T.D., Tucci F.C., Gao Y., Moorjani M., Connors P.J., Rowbottom M.W., Chen Y., Struthers R.S., Xie Q., Saunders J., Reinhart G., Chen T.K., Bonneville A.L.K., and Chen C. J. Med. Chem. 47 (2004) 1259
17. +.