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New Highly Potent and Selective Adenosine A3 Receptor Antagonists

2004; Bentham Science Publishers; Volume: 4; Issue: 8 Linguagem: Inglês

10.2174/1568026043451023

1873-4294

Neil J. Press, Thomas H. Keller, Pamela Tranter, David Beer, Ken Jones, A. FAESSLER, Richard Heng, Christine A. Lewis, Trevor Howe, Peter Gedeck,

Synthesis and Biological Evaluation

A class of potent, selective adenosine A(3) 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 A(3) receptor. Structure activity relationship studies led to both potent and selective A(3) receptor antagonists, including N-[5-pyridin-4-yl-4-(3,4,5-trimethoxyphenyl)-thiazol-2-yl]-acetamide, a highly potent aden-osine A(3) receptor antagonist with greater than 100- fold selectivity against the related adenosine receptors. As well as demonstrating selective in vitro binding on the human A(3) adenosine receptor, this compound was also shown to selectively block the rat A(3) receptor in vivo. This important new compound can be readily synthesised in four steps from commercially available starting materials.