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Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: Prime side chromane-containing inhibitors |
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| Authors: | 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 Ted A Yednock |
| Institution: | 1. Department of Chemical Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA;2. Department of Molecular Design, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA;3. Department of Pharmacological Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA |
| Abstract: | The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1′ region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2′ 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. |
| Keywords: | Beta-secratase inhibitor BACE-1 Alzheimer’s disease Cat-D Chromane Hydroxyethylamine |
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