title: Design and synthesis of calpain inhibitory 6-pyridone 2-carboxamide derivatives.
abstract: Excessive calpain activation contributes to serious cellular damage in many pathological conditions. The involvement of mu-calpain in neurological disorders such as, stroke and Alzheimer's disease has attracted considerable interest in the use of calpain inhibitors as therapeutic agents. 6-Pyridone 2-carboxamides derived from ketoamides were synthesized as conformationally constrained structures resembling the well known peptidic mu-calpain inhibitor, MDL 28,170, and their mu-calpain inhibitory activities were evaluated. Of the compounds synthesized, compound 2a, which has a primary amide at warhead region of the inhibitor most potently inhibited mu-calpain with an IC(50) value of 2.81+/-1.26 microM, which is ca. 40-fold less than that of MDL 28,170.
authors.affiliation: Kyung Hee East-West Pharmaceutical Research Institute, Department of Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Ki Yong
authors.initials: KY
authors.lastname: Lee
authors.forename: Kwang Seob
authors.initials: KS
authors.lastname: Lee
authors.forename: Changbae
authors.initials: C
authors.lastname: Jin
authors.forename: Yong Sup
authors.initials: YS
authors.lastname: Lee
mesh_terms: D002154:Calpain / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D015195:Drug Design; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D015853:Cysteine Proteinase Inhibitors; D011728:Pyridones; D002154:Calpain