Nonnucleoside inhibitors of adenosine kinase.
Adenosine (ADO) is an endogenous inhibitory neuromodulator that increases nociceptive thresholds in response to tissue trauma and inflammation. Adenosine kinase (AK) is a key intracellular enzyme regulating intra- and extracellular concentrations of ADO. AK inhibition selectively amplifies extracellular ADO levels at cell and tissue sites where accelerated release of ADO occurs. AK inhibitors have been shown to provide effective antinociceptive, antiinflammatory and anticonvulsant activity in animal models, thus suggesting their potential therapeutic utility for pain, inflammation, epilepsy and possibly other central and peripheral nervous system diseases associated with cellular trauma and inflammation. This beneficial outcome may potentially lack nonspecific effects associated with the systemic administration of ADO receptor agonists. Until recently all of the reported AK inhibitors contained adenosine-like structural motif. The present review will discuss design, synthesis and analgesic and antiinflammatory properties of the novel nonnucleoside AK inhibitors that do not have close structural resemblance with the natural substrate ADO. Two classes of the nonnucleoside AK inhibitors are built on pyridopyrimidine and alkynylpyrimidine cores.
Gomtsyan
Arthur
A
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. arthur.r.gomtsyan@abbott.com
Lee
Chih-Hung
CH
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D004827:Epilepsy / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy / Q000201:enzymology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011743:Pyrimidines; D000248:Adenosine Kinase