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Bioorg Med Chem Lett. 2014 Dec 1;24(23):5455-9. doi: 10.1016/j.bmcl.2014.10.006. Epub 2014 Oct 23.

Discovery of potent iminoheterocycle BACE1 inhibitors.

Author information

1
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: john.caldwell@merck.com.
2
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.

Abstract

The synthesis of a series of iminoheterocycles and their structure-activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Aβ40 levels upon subcutaneous and oral administration to rats.

KEYWORDS:

Alzheimer’s disease; Aspartyl protease inhibitors; BACE; Structure-based drug design; β-Secretase

PMID:
25455483
DOI:
10.1016/j.bmcl.2014.10.006
[Indexed for MEDLINE]

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