title: 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.
authors.affiliation: Research Laboratory, Senju Pharmaceutical Co, Ltd, 1-5-4Murotani Nishiku, Kobe 651-2241, Japan. masayuki-nakamura@senju.co.jp
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyashita
authors.forename: Masazumi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shirasaki
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
mesh_terms: D000818:Animals; D002154:Calpain / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D003315:Cornea / Q000378:metabolism*; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D009025:Morpholines / Q000494:pharmacology*; D010539:Permeability; D011817:Rabbits; D012995:Solubility; D013552:Swine; D014867:Water / Q000737:chemistry
chemical_list: D009025:Morpholines; D014867:Water; D002154:Calpain; D002401:Cathepsin B