Exploration of cornea permeable calpain inhibitors as anticataract agents.
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.
Nakamura
Masayuki
M
Research Laboratory, Senju Pharmaceutical Co., Ltd., 1-5-4 Murotani Nishiku Kobe 651-2241, Japan. masayuki-nakamura@senju.co.jp
Yamaguchi
Masazumi
M
Sakai
Osamu
O
Inoue
Jun
J
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
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