title: Novel cell-penetrating alpha-keto-amide calpain inhibitors as potential treatment for muscular dystrophy.
abstract: Dipeptide-derived alpha-keto-amide compounds with potent calpain inhibitory activity have been identified. These reversible covalent inhibitors have IC(50) values down to 25nM and exhibit greatly improved activity in muscle cells compared to the reference compound MDL28170. Several novel calpain inhibitors have shown positive effects on histological parameters in an animal model of Duchenne muscular dystrophy demonstrating their potential as a treatment option for this fatal disease.
authors.affiliation: Medicinal Chemistry Department, Santhera Pharmaceuticals, Hammerstrasse 25, CH-4410 Liestal, Switzerland. cyrille.lescop@santhera.com
authors.forename: Cyrille
authors.initials: C
authors.lastname: Lescop
authors.forename: Holger
authors.initials: H
authors.lastname: Herzner
authors.forename: Hervé
authors.initials: H
authors.lastname: Siendt
authors.forename: Reto
authors.initials: R
authors.lastname: Bolliger
authors.forename: Marco
authors.initials: M
authors.lastname: Henneböhle
authors.forename: Philipp
authors.initials: P
authors.lastname: Weyermann
authors.forename: Alexandre
authors.initials: A
authors.lastname: Briguet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Courdier-Fruh
authors.forename: Michael
authors.initials: M
authors.lastname: Erb
authors.forename: Mark
authors.initials: M
authors.lastname: Foster
authors.forename: Thomas
authors.initials: T
authors.lastname: Meier
authors.forename: Josef P
authors.initials: JP
authors.lastname: Magyar
authors.forename: Andreas
authors.initials: A
authors.lastname: von Sprecher
mesh_terms: D000577:Amides / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use*; D003964:Diaphragm / Q000187:drug effects / Q000473:pathology; D004151:Dipeptides / Q000737:chemistry*; D051379:Mice; D018101:Mice, Inbred mdx; D015394:Molecular Structure; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000201:enzymology
chemical_list: D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D002154:Calpain