A β-fluoroamine inhibitor of purine nucleoside phosphorylase

Jennifer M. Mason, Andrew S. Murkin, Lei Li, Vern L. Schramm, Graeme J. Gainsford, Brian W. Skelton

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

The potent immucillin purine nucleoside phosphorylase (PNP) inhibitors F-DADMe-ImmH [(3S,4S)-3], and [(3R,4R)-3] are synthesized in seven steps. Cycloaddition to a fluoroalkene and an enzymic resolution are the key features of the construction of the fluoropyrrolidines 11, from which the immucillins are assembled by use of a three-component Mannich reaction. Slow-onset binding constants (Ki*) for [(3S,4S)-3] and [(3R,4R)-3] with human PNP are 0.032 and 1.82 nM, respectively. F-DADMe-ImmH [(3S,4S)-3] exhibits oral availability in mice at doses as low as 0.2 mg/kg.

Original languageEnglish (US)
Pages (from-to)5880-5884
Number of pages5
JournalJournal of Medicinal Chemistry
Volume51
Issue number18
DOIs
StatePublished - Sep 25 2008

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Mason, J. M., Murkin, A. S., Li, L., Schramm, V. L., Gainsford, G. J., & Skelton, B. W. (2008). A β-fluoroamine inhibitor of purine nucleoside phosphorylase. Journal of Medicinal Chemistry, 51(18), 5880-5884. https://doi.org/10.1021/jm800792b