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Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position.

Abstract：

:Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors possessing a heterocyclic scaffold at the P(2) position. By studying the structure-activity relationship of these inhibitors, we found that the σ-π interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their P(2) regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P(2) position are described along with the results of the related structure-activity relationship study. These small-sized inhibitors are expected improved membrane permeability and bioavailability.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Hamada Y,Nakanishi T,Suzuki K,Yamaguchi R,Hamada T,Hidaka K,Ishiura S,Kiso Y

doi

10.1016/j.bmcl.2012.05.089

subject

Has Abstract

pub_date

2012-07-15 00:00:00

pages

4640-4

issue

14

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(12)00701-9

journal_volume

22

pub_type

杂志文章

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