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Lewis D. Pennington Douglas A. Whittington Michael D. Bartberger Steven R. Jordan Holger Monenschein Thomas T. Nguyen Bryant H. Yang Qiufen M. Xue Filisaty Vounatsos Robert C. Wahl Kui Chen Stephen Wood Martin Citron Vinod F. Patel Stephen A. Hitchcock Wenge Zhong 《Bioorganic & medicinal chemistry letters》2013,23(15):4459-4464
We describe a systematic study of how macrocyclization in the P1–P3 region of hydroxyethylamine-based inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid β-peptide (Aβ)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme. 相似文献
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Marie-Isabel Aguilar Gary D. Fallon Penelpe A. Mayes Sofia Nordin Andrea J. Robinson Mark L. Rose Filisaty Vounatsos Bradley Wilman Patrick Perlmutter 《International journal of peptide research and therapeutics》2003,10(5-6):597-604
Two approaches, based on imino-aldol additions, to the asymmetric synthesis of cyclic β-amino acids are reported. In each case a chiral auxiliary was employed attached either to the enolate or to the imine. The
relative efficacy of these two synthetic methods is also briefly compared with the former still the preferred route as the
latter is currently limited to the preparation of N-sulfonyl β-amino acids. 相似文献
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