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J Med Chem. 2007 Sep 6;50(18):4261-4. Epub 2007 Aug 8.

2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead.

Author information

1
Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, Pennsylvania 19477, USA. ebaxter@prdus.jnj.com

Abstract

A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.

PMID:
17685503
DOI:
10.1021/jm0705408
[Indexed for MEDLINE]

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