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Bioorg Med Chem Lett. 2010 Apr 1;20(7):2068-73. doi: 10.1016/j.bmcl.2010.02.075. Epub 2010 Feb 23.

Novel pyrrolyl 2-aminopyridines as potent and selective human beta-secretase (BACE1) inhibitors.

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Department of Chemical Sciences, Wyeth, CN 8000, Princeton, NJ 08543-8000, USA.


The proteolytic enzyme beta-secretase (BACE1) plays a central role in the synthesis of the pathogenic beta-amyloid in Alzheimer's disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhibitors. However, many of these acylguanidines have a high polar surface area (e.g. as measured by the topological polar surface area or TPSA), which is unfavorable for crossing the blood-brain barrier. Herein, we describe the identification of the 2-aminopyridine moiety as a bioisosteric replacement of the acylguanidine moiety, which resulted in inhibitors with lower TPSA values and superior brain penetration. X-ray crystallographic studies indicated that the 2-aminopyridine moiety interacts directly with the catalytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding network.

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