title: Exploration of cornea permeable calpain inhibitors as anticataract agents.
abstract: To explore cornea permeable calpain inhibitors, four compounds displaying different characteristics were designed and synthesized based on the known potent calpain inhibitor, peptidyl aldehyde SJA6017. Two approaches were adopted; an improvement in the physicochemical properties, and conversion of the active aldehyde. The water-soluble peptidyl aldehyde 1 containing a pyridine ring at the P3 site showed a modest inhibition against calpains and an improvement of corneal permeability in comparison with SJA6017. Replacement of the aldehyde of SJA6017 by an alpha-ketoamide provided compound 2 that was approximately equipotent with SJA6017, but it was extremely water-insoluble. However, compound 3, in which the aldehyde was converted into a cyclic hemiacetal, proved to be a less potent calpain inhibitor than SJA6017, but demonstrated excellent transcorneal permeability. Further modification generating the cyclic hemiacetal 4 containing a thiourea linker between the P3 and P2 sites exhibited potent inhibitory activities, high cornea permeability and excellent efficacy in the rat lens culture cataract model.
authors.affiliation: Research Laboratory, Senju Pharmaceutical Co., Ltd., 1-5-4 Murotani Nishiku Kobe 651-2241, Japan. masayuki-nakamura@senju.co.jp
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Masazumi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Sakai
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors*; D002386:Cataract / Q000188:drug therapy*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003315:Cornea / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D004151:Dipeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D007202:Indicators and Reagents; D007908:Lens, Crystalline / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism; D009883:Ophthalmic Solutions; D009924:Organ Culture Techniques; D010539:Permeability; D011480:Protease Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013890:Thiourea / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000447:Aldehydes; D004151:Dipeptides; D007202:Indicators and Reagents; D009097:Multienzyme Complexes; C109145:N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal; D009883:Ophthalmic Solutions; D011480:Protease Inhibitors; D002154:Calpain; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D013890:Thiourea