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J Med Chem. 2008 Sep 25;51(18):5880-4. doi: 10.1021/jm800792b.

A beta-fluoroamine inhibitor of purine nucleoside phosphorylase.

Author information

1
Carbohydrate Chemistry Team, Industrial Research Limited, P O Box 31310, Lower Hutt, New Zealand. j.mason@irl.cri.nz

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.

PMID:
18800772
PMCID:
PMC4508846
DOI:
10.1021/jm800792b
[Indexed for MEDLINE]
Free PMC Article

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