| Literature DB >> 20973483 |
Brian C Shook1, Stefanie Rassnick, Melville C Osborne, Scott Davis, Lori Westover, Jamie Boulet, Daniel Hall, Kenneth C Rupert, Geoffrey R Heintzelman, Kristin Hansen, Devraj Chakravarty, James L Bullington, Ronald Russell, Shawn Branum, Kenneth M Wells, Sandra Damon, Scott Youells, Xun Li, Derek A Beauchamp, David Palmer, Mayra Reyes, Keith Demarest, Yuting Tang, Kenneth Rhodes, Paul F Jackson.
Abstract
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.Entities:
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Year: 2010 PMID： 20973483 DOI： 10.1021/jm100971t
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446