Synthesis and SAR of indole-and 7-azaindole-1,3-dicarboxamide hydroxyethylamine inhibitors of BACE-1 |
| |
Authors: | Marcin Lawrence R Higgins Mendi A Zusi F Christopher Zhang Yunhui Dee Michael F Parker Michael F Muckelbauer Jodi K Camac Daniel M Morin Paul E Ramamurthy Vidhyashankar Tebben Andrew J Lentz Kimberley A Grace James E Marcinkeviciene Jovita A Kopcho Lisa M Burton Catherine R Barten Donna M Toyn Jeremy H Meredith Jere E Albright Charles F Bronson Joanne J Macor John E Thompson Lorin A |
| |
Affiliation: | Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA. lawrence.marcin@bms.com |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|