| Literature DB >> 21078556 |
Lawrence R Marcin1, Mendi A Higgins, F Christopher Zusi, Yunhui Zhang, Michael F Dee, Michael F Parker, Jodi K Muckelbauer, Daniel M Camac, Paul E Morin, Vidhyashankar Ramamurthy, Andrew J Tebben, Kimberley A Lentz, James E Grace, Jovita A Marcinkeviciene, Lisa M Kopcho, Catherine R Burton, Donna M Barten, Jeremy H Toyn, Jere E Meredith, Charles F Albright, Joanne J Bronson, John E Macor, Lorin A Thompson.
Abstract
Heterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1 inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme inhibition, but displayed poor cellular activity. Improvements in cellular activity and aspartic protease selectivity were observed for 7-azaindole-1,3-dicarboxamide HEAs. A methylprolinol-bearing derivative (10n) demonstrated robust reductions in rat plasma Aβ levels, but did not lower rat brain Aβ due to poor central exposure. The same analog exhibited a high efflux ratio in a bidirectional Caco-2 assay and was likely a substrate of the efflux transporter P-glycoprotein. X-ray crystal structures are reported for two indole HEAs in complex with BACE-1.Entities:
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Year: 2011 PMID： 21078556 DOI： 10.1016/j.bmcl.2010.10.079
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823