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Novel 6-hydroxy-3-morpholinones as cornea permeable calpain inhibitors.

Abstract：

:A novel series of 6-hydroxy-3-morpholinones, in which the functional aldehyde and the hydroxy group of P(2) site form a cyclic hemiacetal, was identified as calpain inhibitors. The placement of isobutyl group at the 2-position of the 3-morpholinone was the most effective modification for inhibiting micro- and m-calpains. Substitutions of benzyl at the 5-position in the S-configuration had virtually no effect on inhibitory activity. Several compounds showed appreciable selectivity for calpains over cathepsin B. NMR experiments demonstrated that the representative 6-hydroxy-3-morpholinone 10a (SNJ-1757) was more stable to nucleophilic attack than the corresponding aldehyde inhibitor 24. Furthermore, 6-hydroxy-3-morpholinone 10a proved to have better corneal permeability than aldehyde inhibitor 24 in an in vitro experiment.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Nakamura M,Miyashita H,Yamaguchi M,Shirasaki Y,Nakamura Y,Inoue J

doi

10.1016/j.bmc.2003.09.031

subject

Has Abstract

pub_date

2003-12-01 00:00:00

pages

5449-60

issue

24

eissn

0968-0896

issn

1464-3391

pii

S0968089603006564

journal_volume

11

pub_type

杂志文章

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