Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 18, Issue 2, Pages 767-771Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2007.11.043
Keywords
BACE-1; amyloid peptide; A beta peptide; aspartyl protease inhibitor; BACE-1 inhibitor; Alzheimer's disease
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The proteolytic enzyme beta-secretase (BACE-1) produces amyloid beta(A beta) peptide, the primary constituent of neurofibrillary plaques, implicated in Alzheimer's disease, by cleavage of the amyloid precursor protein. A small molecule inhibitor of BACE-1, (diaminomethylene)-2,5-diphenyl-1H-pyrrole-1-acetamide (1, BACE-1 IC50 = 3.7 mu M), was recently described, representing a new small molecule lead. Initial SAR investigation demonstrated the potential of accessing the nearby S-3 and S-1' substrate binding pockets of the BACE-1 enzyme by building substituents off one of the phenyl substituents and guanidinyl functional group. We report here the optimization of guanidinyl functional group substituents on 1, leading to potent submicromolar BACE-1 inhibitors. (c) 2007 Elsevier Ltd. All rights reserved.
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