Structure-based design of cycloamide-urethane-derived novel inhibitors of human brain memapsin 2 (beta-secretase).
A series of novel macrocyclic amide-urethanes was designed and synthesized based upon the X-ray crystal structure of our lead inhibitor (1, OM99-2 with eight residues) bound to memapsin 2. Ring size and substituent effects have been investigated. Cycloamide-urethanes containing 14- to 16-membered rings exhibited low nanomolar inhibitory potencies against human brain memapsin 2 (beta-secretase).
Ghosh
Arun K
AK
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607, USA. arunghos@uic.edu
Devasamudram
Thippeswamy
T
Hong
Lin
L
DeZutter
Christopher
C
Xu
Xiaoming
X
Weerasena
Vajira
V
Koelsch
Gerald
G
Bilcer
Geoffrey
G
Tang
Jordan
J
D000577:Amides / Q000737:chemistry*; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001921:Brain / Q000201:enzymology*; D018360:Crystallography, X-Ray; D010450:Endopeptidases; D006801:Humans; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D014520:Urethane / Q000737:chemistry*
D000577:Amides; D011480:Protease Inhibitors; D014520:Urethane; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human