Chem: a1 structures of hypoxanthine and two ant-~ neti-dites derived from this compound, 6 MP and azathioprine. A s discussed, the latter represents a structural modification of 6 MP in which an imidazole side chain has been added to the basic structure of 6 MP. that it possessed immunosuppressive activities (2). Azathioprine was synthesized in 1961; it was reasoned that addition of an imidazole side group to 6 MP would delay metabolism and result in a compound with a longer duration of action (3). However, experimental studies did not bear out this concept. In mice, approximately 70% of an intravenous dose of azathioprine is converted to 6 M p within five minutes (4). This process is non-enzymatic, but can be accelerated by sulfhydryl-containing compounds such as glutathione. Small amounts of azathioprine may be degraded by alternate pathways. It has been postulated that compounds generated in these alternate reactions may have intrinsic immunosuppressive properties which are distinct from those related to 6 MP (5). The biochemistry and pharmacology of the thiopurines have been extensively reviewed (6-12); the major findings are summarized below. These compounds act, by competitive enzyme inhibition, to suppress de novo purine synthesis. The normal metabolic pathway for generating purine bases is shown in figure 2; the central compound in this sequence is inosinic acid (IMP). This nucleotide