1. Synthesis and SAR of indole-and 7-azaindole-1,3-dicarboxamide hydroxyethylamine inhibitors of BACE-1.
- Author
-
Marcin LR, Higgins MA, Zusi FC, Zhang Y, Dee MF, Parker MF, Muckelbauer JK, Camac DM, Morin PE, Ramamurthy V, Tebben AJ, Lentz KA, Grace JE, Marcinkeviciene JA, Kopcho LM, Burton CR, Barten DM, Toyn JH, Meredith JE, Albright CF, Bronson JJ, Macor JE, and Thompson LA
- Subjects
- Amines chemical synthesis, Amines pharmacology, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Peptides blood, Animals, Aspartic Acid Endopeptidases metabolism, Binding Sites, Crystallography, X-Ray, Indoles chemistry, Indoles pharmacology, Protease Inhibitors chemical synthesis, Protease Inhibitors pharmacology, Protein Structure, Tertiary, Pyridines chemistry, Pyridines pharmacology, Rats, Structure-Activity Relationship, Amines chemistry, Amyloid Precursor Protein Secretases antagonists & inhibitors, Aspartic Acid Endopeptidases antagonists & inhibitors, Indoles chemical synthesis, Protease Inhibitors chemistry, Pyridines chemical synthesis
- 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., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF