Adenosine kinase inhibitors. 3. Synthesis, SAR, and antiinflammatory activity of a series of l-lyxofuranosyl nucleosides.
Chronic inflammatory diseases, such as arthritis and rheumatoid arthritis, remain major health problems worldwide. We previously demonstrated that adenosine kinase inhibitors (AKIs) exhibit antiinflammatory effects by inhibiting TNF-alpha production, neutrophil accumulation, and edema formation. Although adenosine receptor agonists produce similar effects, AKIs showed the antiinflammatory activity without the cardiovascular side effects that prevented the development of adenosine receptor specific agonists. However, previously described potent AKIs, such as 5-iodotubercidin, are nucleosides which have the potential to undergo in vivo 5'-O-phosphorylation and therefore produce cytotoxicity. In an effort to eliminate toxicities produced by phosphorylated nucleosides, l-lyxofuranosyl analogues of tubercidin were tested as potential AKIs since the opposite stereochemical orientation of the CH(2)OH was expected to eliminate intracellular phosphorylation. Described herein are the discovery of a new series of AKIs based on alpha-l-lyxofuranosyl nucleosides, their SAR, as well as the antiinflammatory activity of the lead compound GP790 (IC(50) = 0.47 nM, 47% inhibition of paw swelling at 10 mg/kg in rat carrageenan paw edema model). In addition, a study showing that in the skin lesion model the antiinflammatory activity is reversed by an A2 selective adenosine receptor antagonist 3,7-dimethyl-1-propargyl xanthine [correction of propylxanthine] (DMPX) is also described.
Ugarkar
Bheemarao G
BG
Metabasis Therapeutics, Inc., 9390 Towne Centre Drive, San Diego, California 92121, USA. ugarkar@mbasis.com
Castellino
Angelo J
AJ
DaRe
Jay S
JS
Ramirez-Weinhouse
Michele
M
Kopcho
Joseph J
JJ
Rosengren
Sanna
S
Erion
Mark D
MD
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy; D007958:Leukocyte Count; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013329:Structure-Activity Relationship; D013805:Theobromine / Q000031:analogs & derivatives* / Q000494:pharmacology
C478625:5-phenyl-4-N-phenylamino-7-lyxofuranosylpyrrolo(2,3-d)pyrimidine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009705:Nucleosides; D058915:Purinergic P1 Receptor Antagonists; C057837:3,7-dimethyl-1-propargylxanthine; D000248:Adenosine Kinase; D013805:Theobromine