Novel dual inhibitors of calpain and lipid peroxidation with enhanced cellular activity.
A series of dipeptides with dual inhibitory activities on calpain and lipid peroxidation were prepared to target the intracellular calpain. This optimization program focused on the variations of the linker and the N-terminal amino acid of the peptidic core. Two compounds 6d-05 and 6d-08 exhibited potent intracellular calpain inhibition. The polar surface area and the number of rotors appeared to be critical descriptors to account for the behavior of these hybrid molecules in the cellular calpain assay.
Auvin
Serge
S
Department of Medicinal Chemistry, Ipsen Research Laboratories, Institut Henri Beaufour, 5 Avenue du Canada, 91966 Les Ulis Cedex, France. serge.auvin@ipsen.com
Pignol
Bernadette
B
Navet
Edith
E
Troadec
Morgane
M
Carré
Denis
D
Camara
José
J
Bigg
Dennis
D
Chabrier
Pierre-E
PE
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy; D006801:Humans; D020128:Inhibitory Concentration 50; D015227:Lipid Peroxidation / Q000187:drug effects*; D008861:Microsomes / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
D000975:Antioxidants; D004151:Dipeptides; D002154:Calpain