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

doi:10.1021/jm800792b

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

Biochemistry

Research output: Contribution to journal › Article › peer-review

47 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 (K_i*) 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 language	English (US)
Pages (from-to)	5880-5884
Number of pages	5
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	18
DOIs	https://doi.org/10.1021/jm800792b
State	Published - Sep 25 2008

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "A β-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.",

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T1 - A β-fluoroamine inhibitor of purine nucleoside phosphorylase

AU - Mason, Jennifer M.

AU - Murkin, Andrew S.

AU - Li, Lei

AU - Schramm, Vern L.

AU - Gainsford, Graeme J.

AU - Skelton, Brian W.

PY - 2008/9/25

Y1 - 2008/9/25

N2 - 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.

AB - 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.

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A β-fluoroamine inhibitor of purine nucleoside phosphorylase

Abstract

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