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Bioorg Med Chem Lett. 2010 Mar 15;20(6):1885-9. doi: 10.1016/j.bmcl.2010.01.137. Epub 2010 Feb 4.

SAR of tertiary carbinamine derived BACE1 inhibitors: role of aspartate ligand amine pKa in enzyme inhibition.

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  • 1Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. hemaka_rajapakse@merck.com

Abstract

The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pK(a) of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Alphabeta production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.

PMID:
20176482
DOI:
10.1016/j.bmcl.2010.01.137
[PubMed - indexed for MEDLINE]
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