Nucleosides of azathioprine and thiamiprine as antiarthritics.
Azathioprine [Imuran; 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine] is a widely used immunosuppressive and antiarthritic drug. For the sake of comparison, the riboside, the 2'-deoxyriboside, and the arabinoside of azathioprine and its 2-amino congener, thiamiprine, were prepared by an enzymatic method. In vitro, the cytotoxicities of these aglycons and their nucleosides were similar (ED50 = 0.8-2 microM), except for the arabinosides, which were nontoxic (ED50 greater than 100 microM). In vivo, their activities were compared in the rat adjuvant arthritis model. The ribosides and 2'-deoxyribosides were less potent than their corresponding aglycons. The safety indexes of these nucleosides were comparable to those of the corresponding aglycons except for the 2'-deoxyriboside of azathioprine, which had an appreciably lower safety index than did azathioprine. Both arabinosides were inactive and nontoxic. All of the aglycons tested (6-mercaptopurine, azathioprine, 6-thioguanine, and thiamiprine) were of similar potency. However, azathioprine had a more favorable therapeutic index than did 6-mercaptopurine. Similarly, thiamiprine was safer than was 6-thioguanine. In this model, the S-(1-methyl-4-nitro-1H-imidazol-5-yl) moiety imparted greater safety to these thiopurines by decreasing toxicity but not affecting potency.
Krenitsky
T A
TA
Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
Hall
W W
WW
Selph
J L
JL
Truax
J F
JF
Vinegar
R
R
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001169:Arthritis, Experimental / Q000188:drug therapy; D001379:Azathioprine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D009705:Nucleosides / Q000494:pharmacology*; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009705:Nucleosides; C060146:thiamiprine; D001379:Azathioprine