Novel N6-substituted adenosine 5'-N-methyluronamides with high selectivity for human adenosine A3 receptors reduce ischemic myocardial injury.
We recently reported the identification of a novel human adenosine A3 receptor-selective agonist, (2S,3S,4R,5R)-3-amino-5-[6-[5-chloro-2-(3-methylisoxazol-5-ylmethoxy)benzylamino]purin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-608,039), with 1,260-fold selectivity for the human A3 versus human A1 receptor (DeNinno et al., J Med Chem 46: 353-355, 2003). However, because the modest (20-fold) rabbit A3 receptor selectivity of CP-608,039 precludes demonstration of A3-mediated cardioprotection in rabbit models, we identified another member of this class, (2S,3S,4R,5R)-3-amino-5-[6-(2,5-dichlorobenzylamino)purin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-532,903), which both retained human A3 receptor selectivity (210-fold; human A3/human A1 Ki: 23/4,800 nM) and had improved rabbit A3 receptor selectivity (90-fold; rabbit A3/rabbit A1 Ki: 23/2,000 nM). Infarct size was measured in Langendorff hearts or in vivo after 30 min of regional ischemia and 120 min of reperfusion. Five-minute perfusion with CP-532,903 before ischemia-reperfusion elicited a concentration-dependent reduction in infarct size in isolated hearts (EC50: 0.97 nM; maximum reduction in infarct size: 77%, P < 0.05 vs. control). Furthermore, administration of CP-532,903 (150 nM) at reperfusion also significantly reduced infarct size by 64% (P < 0.05 vs. control), which was not different (P > or = 0.05) from the cardioprotection provided by the same concentration of drug given before ischemia. The selective rabbit A1 receptor antagonist BWA1433 did not affect CP-532,903-dependent cardioprotection. In vivo, CP-532,903 (1 mg/kg) reduced infarct size by 50% in the absence of significant hemodynamic effects (mean arterial pressure, heart rate, rate-pressure product). CP-532,903 and CP-608,039 represent a novel class of human A3 receptor-selective agonists that may prove suitable for investigation of the clinical cardioprotective efficacy of A3 receptor activation.
Tracey
W Ross
WR
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, MS8220-3125, Eastern Point Rd., Groton, CT 06340, USA. w_ross_tracey@groton.pfizer.com
Magee
William P
WP
Oleynek
Joseph J
JJ
Hill
Roger J
RJ
Smith
Andrew H
AH
Flynn
David M
DM
Knight
Delvin R
DR
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D058909:Adenosine A3 Receptor Agonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007457:Iodine Radioisotopes; D007555:Isoxazoles / Q000737:chemistry; D009203:Myocardial Infarction / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D011687:Purines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism; D020280:Sertraline / Q000031:analogs & derivatives*; D014162:Transfection
D058909:Adenosine A3 Receptor Agonists; C471165:CP 608039; C479779:CP-532,903; D005663:Furans; D007457:Iodine Radioisotopes; D007555:Isoxazoles; D011687:Purines; D043684:Receptor, Adenosine A3; C065162:desmethylsertraline; D000241:Adenosine; D020280:Sertraline