Discovery of 4-Amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin- 3-yl)pyrido[2,3-d]pyrimidine, an Orally Active, Non-Nucleoside Adenosine Kinase Inhibitor

Adenosine (ADO) is an endogenous homeostatic inhibitory neuromodulator that reduces cellular excitability at sites of tissue injury and inflammation. Inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO, selectively increases ADO concentrations at sites of tissue trauma and enhances the analgesic and antiinflammatory actions of ADO. Optimization of the high-throughput screening lead, 4-amino-7-aryl-substituted pteridine (<BO>5</BO>) (AK IC<INF>50</INF> = 440 nM), led to the identification of compound <BO>21</BO> (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d]pyrimidine, ABT-702), a novel, potent (AK IC<INF>50</INF> = 1.7 nM) non-nucleoside AK inhibitor with oral activity in animal models of pain and inflammation.