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Rational design and synthesis of selective BACE-1 inhibitors |
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| Authors: | Brady Stephen F Singh Satendra Crouthamel Ming Chih Holloway M Katharine Coburn Craig A Garsky Victor M Bogusky Michael Pennington Michael W Vacca Joseph P Hazuda Daria Lai Ming-Tain |
| Institution: | Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. |
| Abstract: | An effective approach for enhancing the selectivity of beta-site amyloid precursor protein cleaving enzyme (BACE 1) inhibitors is developed based on the unique features of the S1' pocket of the enzyme. A series of low molecular weight (<600) compounds were synthesized with different moieties at the P1' position. The selectivity of BACE 1 inhibitors versus cathepsin D and renin was enhanced 120-fold by replacing the hydrophobic propyl group with a hydrophilic propionic acid group. |
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