title: Exploration of orally available calpain inhibitors 2: peptidyl hemiacetal derivatives.
abstract: We previously reported a potent calpain inhibitor 1 (SJA6017, N-(4-fluorophenyl)-l-valyl-l-leucinal), which displayed relatively low oral bioavailability (BA). Replacing the metabolically labile aldehyde moiety of 1with more chemically stable warheads, such as a cyclic hemiacetal, hydrazone, and alpha-ketoamide, provided the inhibitors with improved in vitro metabolic stability. Cyclic hemiacetal 2 was the most stable of these compounds. The optimization of 2 led to hemiacetal 8 (SNJ-1715) which exhibited high potency, good aqueous solubility, excellent oral BA, and prolonged plasma half-life in rats. Furthermore, 8 showed neuroprotective efficacy via oral administration in a rat retinal ischemia model.
authors.affiliation: Senju Pharmaceutical Company, 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: Masayuki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Masazumi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyashita
authors.forename: Osamu
authors.initials: O
authors.lastname: Sakai
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors*; D002460:Cell Line; D004151:Dipeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D007511:Ischemia / Q000473:pathology / Q000517:prevention & control; D008297:Male; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D012164:Retinal Diseases / Q000473:pathology / Q000517:prevention & control; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D004151:Dipeptides; C109145:N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal; D018696:Neuroprotective Agents; C512439:SNJ 1715; D002154:Calpain; D013890:Thiourea