Synthesis and SAR of bis-statine based peptides as BACE 1 inhibitors.
A new series of bis-statine based peptidomimetic inhibitors of human beta-secretase (BACE 1) was developed by structure-based modification of the three regions to the initial lead 3: an N-terminus, a central bis-statine core, and a C-terminus. Introduction of a 4-aminomethylbenzoic acid on the C-terminus resulted in a potent BACE 1 inhibitor with an IC50 value of 21 nM. The general requirements for the optimal substrate-enzyme interaction are disclosed herein.
Hu
Baihua
B
Department of Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. hub@wyeth.com
Fan
Kristi Yi
KY
Bridges
Kristie
K
Chopra
Rajiv
R
Lovering
Frank
F
Cole
Derek
D
Zhou
Ping
P
Ellingboe
John
J
Jin
Guixiang
G
Cowling
Rebecca
R
Bard
Jonathan
J
D010129:4-Aminobenzoic Acid / Q000737:chemistry / Q000494:pharmacology; D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D062366:para-Aminobenzoates
D000596:Amino Acids; D004791:Enzyme Inhibitors; D010455:Peptides; D062366:para-Aminobenzoates; C015668:4-aminomethylbenzoic acid; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D010129:4-Aminobenzoic Acid; C013165:statine