Structure-based design of cycloamide-urethane-derived novel inhibitors of human brain memapsin 2 (beta-secretase)

Arun K Ghosh; Thippeswamy Devasamudram; Lin Hong; Christopher DeZutter; Xiaoming Xu; Vajira Weerasena; Gerald Koelsch; Geoffrey Bilcer; Jordan Tang

doi:10.1016/j.bmcl.2004.10.084

Structure-based design of cycloamide-urethane-derived novel inhibitors of human brain memapsin 2 (beta-secretase)

Bioorg Med Chem Lett. 2005 Jan 3;15(1):15-20. doi: 10.1016/j.bmcl.2004.10.084.

Authors

Arun K Ghosh¹, Thippeswamy Devasamudram, Lin Hong, Christopher DeZutter, Xiaoming Xu, Vajira Weerasena, Gerald Koelsch, Geoffrey Bilcer, Jordan Tang

Affiliation

¹ Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607, USA. [email protected]

PMID: 15582402
DOI: 10.1016/j.bmcl.2004.10.084

Abstract

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).

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Amides / chemistry*
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Brain / enzymology*
Crystallography, X-Ray
Endopeptidases
Humans
Molecular Structure
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacology
Urethane / chemistry*

Substances

Amides
Protease Inhibitors
Urethane
Amyloid Precursor Protein Secretases
Endopeptidases
Aspartic Acid Endopeptidases
BACE1 protein, human

Grants and funding

AG 18933/AG/NIA NIH HHS/United States