Third-generation immucillins: Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase

Keith Clinch, Gary B. Evans, Richard F.G. Frohlich, Richard H. Furneaux, Peter M. Kelly, Laurent Legentil, Andrew S. Murkin, Lei Li, Vern L. Schramm, Peter C. Tyler, Anthony D. Woolhouse

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1126-1143
Number of pages18
JournalJournal of Medicinal Chemistry
Volume52
Issue number4
DOIs
StatePublished - Feb 26 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Clinch, K., Evans, G. B., Frohlich, R. F. G., Furneaux, R. H., Kelly, P. M., Legentil, L., Murkin, A. S., Li, L., Schramm, V. L., Tyler, P. C., & Woolhouse, A. D. (2009). Third-generation immucillins: Syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase. Journal of Medicinal Chemistry, 52(4), 1126-1143. https://doi.org/10.1021/jm801421q