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BACE-1 inhibitors part 2: identification of hydroxy ethylamines (HEAs) with reduced peptidic character |
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| Authors: | Clarke Brian Demont Emmanuel Dingwall Colin Dunsdon Rachel Faller Andrew Hawkins Julie Hussain Ishrut MacPherson David Maile Graham Matico Rosalie Milner Peter Mosley Julie Naylor Alan O'Brien Alistair Redshaw Sally Riddell David Rowland Paul Soleil Virginie Smith Kathrine J Stanway Steven Stemp Geoffrey Sweitzer Sharon Theobald Pam Vesey David Walter Daryl S Ward John Wayne Gareth |
| Affiliation: | Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom. |
| Abstract: | This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures. |
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