Structure-activity studies of 5-substituted pyridopyrimidines as adenosinekinase inhibitors

The synthesis and SAR of a novel series of non-nucleoside pyridopyrimidine inhibitors of the enzyme adenosine kinase (AK) are described. It was found that pyridopyrimidines with a broad range of medium and large non-polar sub stituents at the 5-position potently inhibited AK activity. A narrower rang e of analogues was capable of potently inhibiting adenosine phosphorylation in intact cells indicating an enhanced ability of these analogues to penet rate cell membranes. Potent AK inhibitors were found to effectively reduce nociception in animal models of thermal hyperalgesia and persistent pain. ( C) 2000 Elsevier Science Ltd. All rights reserved.