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Retinal penetration of calpain inhibitors in rats after oral administration.

Abstract
Calpain-mediated proteolysis has been involved in neuronal cell death of retinal neurological degeneration. An aldehyde-based calpain inhibitor, SJA6017 (1), was effective following oral administration in a rat retinal ischemia model but had low oral bioavailability. The aim of this study was to identify calpain inhibitors with good retinal penetration after oral dosing. The orally bioavailable inhibitors, hemiacetal 3 (SNJ-1715), amphipathic ketoamide 5 (SNJ-1945), and pyridine ketoamide 6 (SNJ-2008), were evaluated for their retinal pharmacokinetic (PK) profiles. The retinal drug exposure of these inhibitors was more than tenfold higher than 1. Among these compounds, 5 exhibited the most favorable retinal PK properties, such as good penetration and long half-life. Comparisons of 5 and the structurally related ketoamide 6 suggested that the presence of a methoxy diethylene glycol moiety resulted in the inhibitor with high penetration into the retina and the sustained high retinal levels. Ketoamide 5 was selected as the development candidate for the treatment of retinal diseases.
AuthorsYoshihisa Shirasaki, Masazumi Yamaguchi, Hiroyuki Miyashita
JournalJournal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics (J Ocul Pharmacol Ther) Vol. 22 Issue 6 Pg. 417-24 (Dec 2006) ISSN: 1080-7683 [Print] United States
PMID17238807 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Enzyme Inhibitors
  • Calpain
Topics
  • Administration, Oral
  • Animals
  • Calpain (antagonists & inhibitors)
  • Chromatography, Liquid
  • Enzyme Inhibitors (administration & dosage, chemistry, pharmacokinetics)
  • Half-Life
  • Injections, Intravenous
  • Male
  • Molecular Structure
  • Rats
  • Rats, Sprague-Dawley
  • Retina (metabolism)
  • Structure-Activity Relationship
  • Tandem Mass Spectrometry

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