Structure-based design and synthesis of macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors.
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Machauer, Rainer, Veenstra, Siem, Rondeau, Jean-Michel, Tintelnot-Blomley, Marina, Betschart, Claudia, Neumann, Ulf and Paganetti, Paolo (2009) Structure-based design and synthesis of macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors. Bioorganic & Medicinal Chemistry Letters, 19 (5). pp. 1361-1365. ISSN 1464-3405
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.
| Item Type: | Article |
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| Additional Information: | Author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
| Keywords: | Alzheimer’s disease; BACE-1 inhibition; Macrocyclization; Hydroxyethylene transition-state mimetic |
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| Date Deposited: | 22 Feb 2010 11:50 |
| Last Modified: | 31 Jan 2013 00:50 |
| URI: | https://oak.novartis.com/id/eprint/1798 |