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Bioorg Med Chem Lett. 2010 Jan 15;20(2):632-5. doi: 10.1016/j.bmcl.2009.11.052. Epub 2009 Nov 20.

Discovery and initial optimization of 5,5'-disubstituted aminohydantoins as potent beta-secretase (BACE1) inhibitors.

Author information

1
Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States. nowakp@wyeth.com

Abstract

8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S(1) to the S(3) pocket.

PMID:
19959359
DOI:
10.1016/j.bmcl.2009.11.052
[Indexed for MEDLINE]

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