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Third-generation Immucillins: Syntheses And Bioactivities Of Acyclic Immucillin Inhibitors Of Human Purine Nucleoside Phosphorylase.

K. Clinch, G. B. Evans, Richard F. G. Fröhlich, R. Furneaux, P. Kelly, Laurent Legentil, A. S. Murkin, L. Li, V. Schramm, P. Tyler, A. D. Woolhouse
Published 2009 · Chemistry, Medicine

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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.
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