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

Chemistry

University at Buffalo

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

50 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
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

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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.",

author = "Mason, \{Jennifer M.\} and Murkin, \{Andrew S.\} and Lei Li and Schramm, \{Vern L.\} and Gainsford, \{Graeme J.\} and Skelton, \{Brian W.\}",

year = "2008",

month = sep,

day = "25",

doi = "10.1021/jm800792b",

language = "English",

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TY - JOUR

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.

UR - https://www.scopus.com/pages/publications/52449133195

U2 - 10.1021/jm800792b

DO - 10.1021/jm800792b

M3 - Article

C2 - 18800772

SN - 0022-2623

VL - 51

SP - 5880

EP - 5884

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 18

ER -

A β-fluoroamine inhibitor of purine nucleoside phosphorylase

Abstract

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