Adenosine kinase inhibitors. 1. Synthesis, enzyme inhibition, and antiseizure activity of 5-iodotubercidin analogues.
Adenosine receptor agonists produce a wide variety of therapeutically useful pharmacologies. However, to date they have failed to undergo successful clinical development due to dose-limiting side effects. Adenosine kinase inhibitors (AKIs) represent an alternative strategy, since AKIs may raise local adenosine levels in a more site- and event-specific manner and thereby elicit the desired pharmacology with a greater therapeutic window. Starting with 5-iodotubercidin (IC50 = 0.026 microM) and 5'-amino-5'-deoxyadenosine (IC50 = 0.17 microM) as lead inhibitors of the isolated human AK, a variety of pyrrolo[2,3-d]pyrimidine nucleoside analogues were designed and prepared by coupling 5-substituted-4-chloropyrrolo[2,3-d]pyrimidine bases with ribose analogues using the sodium salt-mediated glycosylation procedure. 5'-Amino-5'-deoxy analogues of 5-bromo- and 5-iodotubercidins were found to be the most potent AKIs reported to date (IC50S < 0.001 microM). Several potent AKIs were shown to exhibit anticonvulsant activity in the rat maximal electric shock (MES) induced seizure assay.
Ugarkar
B G
BG
Metabasis Therapeutics Inc, San Diego, California 92121, USA. ugarkar@mbasis.com
DaRe
J M
JM
Kopcho
J J
JJ
Browne
C E
CE
Schanzer
J M
JM
Wiesner
J B
JB
Erion
M D
MD
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004597:Electroshock; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D013329:Structure-Activity Relationship; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D000248:Adenosine Kinase; D014372:Tubercidin