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Bioorg Med Chem Lett. 2008 Jan 15;18(2):767-71. Epub 2007 Nov 17.

Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1' substrate binding pocket.

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Chemical & Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA.


The proteolytic enzyme beta-secretase (BACE-1) produces amyloid beta (Abeta) 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 IC(50)=3.7 microM), 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.

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