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New Highly Potent and Selective Adenosine A3 Receptor Antagonists

[ Vol. 4 , Issue. 8 ]


Neil J. Press, Thomas H. Keller, Pamela Tranter, David Beer, Ken Jones, Alexander Faessler, Richard Heng, Christine Lewis, Trevor Howe and Peter Gedeck   Pages 863 - 870 ( 8 )


A class of potent, selective adenosine A3 receptor antagonists was obtained via optimisation of the screening hit N-[4-(4-methoxyphenyl)-thiazol-2-yl]-acetamide. Structural modifications of this hit revealed very quickly that a 5-(pyridin-4-yl) substituent on the 2- aminothiazole ring was optimal for high potency at the adenosine A3 receptor. Structure activity relationship studies led to both potent and selective A3 receptor antagonists, including N-[5-pyridin-4-yl-4-(3,4,5-trimethoxyphenyl)-thiazol-2-yl]-acetamide, a highly potent aden-osine A3 receptor antagonist with greater than 100- fold selectivity against the related adenosine receptors. As well as demonstrating selective in vitro binding on the human A3 adenosine receptor, this compound was also shown to selectively block the rat A3 receptor in vivo. This important new compound can be readily synthesised in four steps from commercially available starting materials.


adenosine a3 receptor antagonists, n-[4-(4-methoxyphenyl)-thiazol-2-yl]-acetamide, n-[5-pyridin-4-yl-4-(3,4,5-trimethoxyphenyl)-thiazol-2-yl]-acetamide


Novartis Horsham Research Center, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, UK.

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