A beta-fluoroamine inhibitor of purine nucleoside phosphorylase.
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.
Mason
Jennifer M
JM
Carbohydrate Chemistry Team, Industrial Research Limited, P O Box 31310, Lower Hutt, New Zealand. j.mason@irl.cri.nz
Murkin
Andrew S
AS
Li
Lei
L
Schramm
Vern L
VL
Gainsford
Graeme J
GJ
Skelton
Brian W
BW
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
D000588:Amines; D004791:Enzyme Inhibitors; D011683:Purine-Nucleoside Phosphorylase
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