5‘-Deoxy Congeners of 9-(3-Amido-3-deoxy-β-d-xylofuranosyl)-N 6-cyclopentyladenine:  New Adenosine A1 Receptor Antagonists and Inverse Agonists

• Published in: Journal of medicinal chemistry 2002-04, Vol.45 (9), p.1845-1852
• Main Authors: Van Calenbergh, Serge, Link, Andreas, Fujikawa, Shelly, de Ligt, Rianne A. F, Vanheusden, Veerle, Golisade, Abolfasl, Blaton, Norbert M, Rozenski, Jef, IJzerman, Adriaan P, Herdewijn, Piet
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0110439

The synthesis and structure−activity relationship of N 6-cyclopentyl-3‘-substituted-xylofuranosyladenosine analogues with respect to various adenosine receptors were explored in order to identify selective and potent antagonists and inverse agonists for the adenosine A1 receptor. In particular, the effects of removal of the 5‘-OH group and introduction of selected substituents at the 3‘-NH2 position of 9-(3-amino-3-deoxy-β-d-xylofuranosyl)-N 6-cyclopentyladenine were probed. A solid phase-assisted synthetic approach was used to optimize the 3‘-amide functionality. In view of the general concern of the presence of a 5‘-OH moiety with regard to cellular toxicity, the present study describes 5‘-deoxy compounds with reasonable affinity for the human adenosine A1 receptor. Interestingly, this study shows that optimization of the 3‘-“up” amide sustituent can substantially compensate for the drop in affinity for the adenosine A1 receptor, which is generally observed upon removal of the 5‘-OH group. The fact that for several 3‘-amido-substituted (5‘-deoxy)-N 6-cyclopentyladenosine derivatives, guanosine 5‘-triphosphate-induced shifts in K i values were significantly lower than 1 implies that these analogues behave as inverse agonists. This is further supported by their 1,3-dipropyl-8-cyclopentylxanthine-like capacity to increase forskolin-induced adenosine cyclic 3‘,5‘-phosphate production.