Third-Generation Immucillins: Syntheses and Bio-Activities of Acyclic Immucillin Inhibitors of Human Purine Nucleoside Phosphorylase

ImmH ( 1 ) and DADMe-ImmH ( 2 ) are potent inhibitors of human purine nucleoside phoshorylase (PNP), developed by us and currently in clinical trials for the treatment of a variety of T-cell related diseases. Compounds 1 and 2 were used as templates for the design and synthesis of a series of acyclic immucillin analogues ( 8–38 ) in order to identify simplified alternatives to 1 and 2 . SerMe-ImmG ( 8 ) and DATMe-ImmG ( 9 ) displayed the lowest inhibition constants of 2.1 and 3.4 pM, respectively, vs PNP. It was postulated that the flexible natures of 8 and 9 enabled them to adopt conformations resembling those of 1 and 2 within the active site of PNP and that the positioning of two hydroxyl groups was critical for picomolar activity. SerMe-ImmH ( 10 , K d = 5.2 pM) was shown to be orally available in mice with a long biological residence time on blood PNP.