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Bioorg Med Chem Lett. 2009 Mar 1;19(5):1361-5. doi: 10.1016/j.bmcl.2009.01.036. Epub 2009 Jan 19.

Structure-based design and synthesis of macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors.

Author information

1
Novartis Institutes for BioMedical Research, Novartis Pharma AG, PO Box, CH-4002 Basel, Switzerland.

Erratum in

  • Bioorg Med Chem Lett. 2009 Apr 15;19(8):2366.

Abstract

The hydroxyethylene octapeptide inhibitor OM99-2 served as starting point to create the tripeptide inhibitor 1 and its analogues 2a and b. An X-ray co-crystal structure of 1 with BACE-1 allowed the design and syntheses of a series of macrocyclic analogues 3a-h covalently linking the P1 and P3 side-chains. These inhibitors show improved enzymatic potency over their open-chain analogue. Inhibitor 3h also shows activity in a cellular system.

PMID:
19195886
DOI:
10.1016/j.bmcl.2009.01.036
[Indexed for MEDLINE]

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