In Vivo Characterization of a Dual Adenosine A2A/A1 Receptor Antagonist in Animal Models of Parkinson’s Disease
| Autor: | Brian C. Shook, Kenneth C. Rupert, Stefanie Rassnick, Hall Daniel A, Scott Davis, Sandra Damon, Reyes Mayra B, Lori Westover, Melville C. Osborne, Scott Youells, Yuting Tang, Ronald K. Russell, Keith T. Demarest, Xun Li, Paul F. Jackson, Shawn Branum, Devraj Chakravarty, Derek A. Beauchamp, Kristin Hansen, Kenneth J. Rhodes, David C. Palmer, James L. Bullington, Geoffrey R. Heintzelman, Kenneth M. Wells, Jamie Boulet |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Parkinson's disease Receptor Adenosine A2A Administration Oral Adenosine A1 Receptor Antagonists Pharmacology Catalepsy Antiparkinson Agents Rats Sprague-Dawley Mice Adenosine A1 receptor In vivo Drug Discovery medicine Animals Receptor Mice Inbred BALB C Chemistry Antagonist Callithrix Parkinson Disease medicine.disease Adenosine In vitro Adenosine A2 Receptor Antagonists Rats Disease Models Animal Macaca fascicularis Pyrimidines Indenes Molecular Medicine Female medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 53:8104-8115 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm100971t |
| Popis: | The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model. |
| Databáze: | OpenAIRE |
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