Nucleosides of Azathioprine and Thiamiprine as Antiarthritics

Article abstract of DOI:10.1021/jm00127a013

Azathioprine -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 aglycones and their nucleosides were similar (ED 50 = 0.8-2 μM), except for the arabinoside, which were nontoxic (ED 50 > 100 μM).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 appreciable 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-thiaguanine.In this model, the S-(1-methyl-4-nitro-1H-imidazol-5-yl) moiety impared greater safety to these thiopurines by decreasing toxicity but not affecting potency.