title: Exploration of orally available calpain inhibitors: peptidyl alpha-ketoamides containing an amphiphile at P3 site.
abstract: A novel series of dipeptidyl alpha-ketoamide derivatives with amphiphile was designed and synthesized as water-soluble calpain inhibitors. The introduction of amphiphiles at the P3 site increased water solubility without loss of membrane permeability and provided the oral available inhibitors. Extension of the ethylene glycol chain at the P3 site led to an improvement in persistence of plasma levels. In particular, introduction of a combination of a diethylene glycol methyl ether moiety at the P3 site, a phenylalanine residue at the P1 site and a cyclopropyl moiety at the P' site was the most effective modification for an increase in plasma drug exposure.
authors.affiliation: Research Laboratory of Ocular Science, Senju Pharmaceutical Co., Ltd, 1-5-4 Murotani Nishi-ku Kobe, Hyogo 651-2241, Japan. shirasaki@senju.co.jp
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shirasaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyashita
authors.forename: Masazumi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakamura
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002154:Calpain / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D012995:Solubility; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D002154:Calpain