title: Exploration of orally available calpain inhibitors. Part 3: Dipeptidyl alpha-ketoamide derivatives containing pyridine moiety.
abstract: Calpain-mediated proteolysis has been implicated as a major process in neuronal cell death including retinal neurological degeneration. The previously reported calpain inhibitor SJA6017 (1) showed oral efficacy in a retinal pharmacological model, but its oral bioavailability was low due to the metabolic lability and low water-solubility. The purpose of present study was to identify good orally bioavailable calpain inhibitors. A series of water-soluble dipeptidyl alpha-ketoamides containing a pyridine moiety at P3 were designed, synthesized, and evaluated for their oral bioavailability and retinal penetration. Introduction of a pyridineethanol moiety provided the potent alpha-ketoamide inhibitor 8 with good oral bioavailability. Compound 8 showed about 12-fold higher retinal AUC than 1.
authors.affiliation: Research Laboratory of Ocular Science, Senju Pharmaceutical Co. Ltd, Nishi-ku, Kobe, Hyogo, 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
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002154:Calpain / Q000037:antagonists & inhibitors*; D016923:Cell Death / Q000187:drug effects; D004151:Dipeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D004151:Dipeptides; D018696:Neuroprotective Agents; D011725:Pyridines; D014867:Water; D002154:Calpain; C023666:pyridine