Design, synthesis, and evaluation of fused heterocyclic analogs of SCH 58261 as adenosine A2A receptor antagonists |
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Authors: | Shah Unmesh Lankin Claire M Boyle Craig D Chackalamannil Samuel Greenlee William J Neustadt Bernard R Cohen-Williams Mary E Higgins Guy A Ng Kwokei Varty Geoffrey B Zhang Hongtao Lachowicz Jean E |
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Affiliation: | aSchering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA |
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Abstract: | SCH 58261 is a reported adenosine A2A receptor antagonist which is active in rat in vivo models of Parkinson’s Disease upon ip administration. However, it has poor selectivity versus the A1 receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A2A receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A2A receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson’s Disease, and has aqueous solubility of 100 μM at physiological pH. |
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Keywords: | Adenosine A2A A2A receptor A2A antagonist A2A receptor antagonist SCH 58261 Parkinson’ s Disease |
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