Molecular modeling, synthesis, and biological evaluation of macrocyclic calpain inhibitors.
The design and elaboration of a series of macrocyclic templates that exhibit a propensity to adopt a beta-strand-like peptide-backbone conformation led to potent and selective inhibitors of calpain 2. Macrocycle 1 retarded calcium-induced opacification in an ovine-lens culture assay and is a lead compound for the development of a drug for cataract treatment. Cbz=carbobenzyloxy.
Abell
Andrew D
AD
Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, New Zealand.
Jones
Matthew A
MA
Coxon
James M
JM
Morton
James D
JD
Aitken
Steven G
SG
McNabb
Stephen B
SB
Lee
Hannah Y-Y
HY
Mehrtens
Janna M
JM
Alexander
Nathan A
NA
Stuart
Blair G
BG
Neffe
Axel T
AT
Bickerstaffe
Roy
R
D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002386:Cataract / Q000139:chemically induced / Q000188:drug therapy; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007908:Lens, Crystalline / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D012756:Sheep; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D006571:Heterocyclic Compounds; D047028:Macrocyclic Compounds; C106058:macrocycle 1; D002154:Calpain