Hit-to-lead optimization of a series of carboxamides of ethyl 2-amino-4-phenylthiazole-5-carboxylates as novel adenosine A2A receptor antagonists.

Abstract

Herein we describe the discovery of a series of novel adenosine A(2A) receptor antagonists. A successful hit-to-lead optimization of an HTS hit led to replacement of a metabolically labile ester moiety with a heteroaromatic group. A compound from the series, (cyclopropanecarboxylic acid [5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-yl]-amide, compound 13), was shown to be effective in reversing haloperidol-induced hypolocomotion, a model of motor dysfunction in Parkinson's Disease.

• Authors: Anette Graven Sams, Gitte Kobberøe Mikkelsen, Mogens Larsen, Lars Torup, Lise Tøttrup Brennum, Tenna Juul Schrøder, Benny Bang-Andersen
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 20 Issue 17 Pg. 5241-4 (Sep 01 2010) ISSN: 1464-3405 [Electronic] England
• PMID: 20659802 (Publication Type: Journal Article)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Amides
• Carboxylic Acids
• Purinergic P1 Receptor Antagonists
• Receptor, Adenosine A2A

Topics

• Amides (chemistry, pharmacology)
• Carboxylic Acids (chemistry, pharmacology)
• Purinergic P1 Receptor Antagonists (chemistry, pharmacology)
• Receptor, Adenosine A2A (drug effects)
• Structure-Activity Relationship