Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: Prime side chromane-containing inhibitors
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- 作者：Raymond A. Ng ; Minghua Sun ; Simeon Bowers ; Roy K. Hom ; Gary D. Probst ; Varghese John ; Lawrence Y. Fang ; Michel Maillard ; Andrea Gailunas ; Louis Brogley ; R. Jeffrey Neitz ; Jay S. Tung ; Michael A. Pleiss ; Andrei W. Konradi ; Hing L. Sham ; Michael S. Dappen ; Marc Adler ; Nanhua Yao ; Wes Zmolek ; David Nakamura ; et al.
- 关键词：Beta-secratase inhibitor ; BACE-1 ; Alzheimer&rsquo ; s disease ; Cat-D ; Chromane ; Hydroxyethylamine
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：15 August, 2013
- 年：2013
- 卷：23
- 期：16
- 页码：4674-4679
- 全文大小：1137 K
文摘
The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1¡ä region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2¡ä substituent of chromane-HEA(s) with polar substituents provided improvements in the compound¡¯s in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.