Biaryl and heteroaryl derivatives of SCH 58261 as potent and selective adenosine A2A receptor antagonists

SCH 58261 is a reported adenosine A(2A) receptor antagonist, which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. We report the design and synthesis of biaryl and he...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2008-07, Vol.18 (14), p.4199-4203
Main Authors: SHAH, Unmesh, BOYLE, Craig D, SHIYONG WANG, MONOPOLI, Angela, LACHOWICZ, Jean E, CHACKALAMANNIL, Samuel, NEUSTADT, Bernard R, LINDO, Neil, GREENLEE, William J, FOSTER, Carolyn, ARIK, Leyla, YING ZHAI, NG, Kwokei
Format: Article
Language:English
Subjects:
Adenosine A2 Receptor Antagonists
Administration, Oral
Animals
Behavior, Animal - drug effects
Biological and medical sciences
Chemistry, Pharmaceutical - methods
Drug Design
Humans
Medical sciences
Models, Chemical
Neuropharmacology
Neuroprotective Agents - chemical synthesis
Neuroprotective Agents - pharmacology
Neurotransmitters. Neurotransmission. Receptors
Parkinson Disease - drug therapy
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Piperazines - chemistry
Pyrimidines - chemical synthesis
Pyrimidines - pharmacology
Quinolines - chemistry
Rats
Structure-Activity Relationship
Triazoles - chemical synthesis
Triazoles - pharmacology
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Summary:SCH 58261 is a reported adenosine A(2A) receptor antagonist, which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. We report the design and synthesis of biaryl and heteroaryl analogs of SCH 58261 which improve the A(2A) receptor binding selectivity as well as the pharmacokinetic properties of SCH 58261. In particular, the quinoline 25 has excellent A(2A) receptor in vitro binding affinity and selectivity, sustained rat plasma levels upon oral dosing, and is active orally in a rat behavioral assay.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2008.05.074