title: A beta-fluoroamine inhibitor of purine nucleoside phosphorylase.
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.
authors.affiliation: Carbohydrate Chemistry Team, Industrial Research Limited, P O Box 31310, Lower Hutt, New Zealand. j.mason@irl.cri.nz
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Mason
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Murkin
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Gainsford
authors.forename: Brian W
authors.initials: BW
authors.lastname: Skelton
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000588:Amines; D004791:Enzyme Inhibitors; D011683:Purine-Nucleoside Phosphorylase
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