Novel cell-penetrating alpha-keto-amide calpain inhibitors as potential treatment for muscular dystrophy.
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.
Lescop
Cyrille
C
Medicinal Chemistry Department, Santhera Pharmaceuticals, Hammerstrasse 25, CH-4410 Liestal, Switzerland. cyrille.lescop@santhera.com
Herzner
Holger
H
Siendt
Hervé
H
Bolliger
Reto
R
Henneböhle
Marco
M
Weyermann
Philipp
P
Briguet
Alexandre
A
Courdier-Fruh
Isabelle
I
Erb
Michael
M
Foster
Mark
M
Meier
Thomas
T
Magyar
Josef P
JP
von Sprecher
Andreas
A
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
D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D002154:Calpain