15 research outputs found
Destruxin E Decreases Beta-Amyloid Generation by Reducing Colocalization of Beta-Amyloid-Cleaving Enzyme 1 and Beta-Amyloid Protein Precursor
Alzheimer-disease-associated beta-amyloid (A beta) is produced by sequential endoproteolysis of beta-amyloid protein precursor (beta APP): the extracellular portion is shed by cleavage in the juxtamembrane region by beta-amyloid-cleaving enzyme (BACE)/beta-secretase, after which it is cleaved by presenilin (PS)/gamma-secretase near the middle of the transmembrane domain. Thus, inhibition of either of the secretases reduces A beta generation and is a fundamental strategy for the development of drugs to prevent Alzheimer disease. However, it is not clear how small compounds reduce A beta production without inhibition of the secretases. Such compounds are expected to avoid some of the side effects of secretase inhibitors. Here, we report that destruxin E (Dx-E), a natural cyclic hexadepsipeptide, reduces A beta generation without affecting BACE or PS/gamma-secretase activity. In agreement with this, Dx-E did not inhibit Notch signaling. We found that Dx-E decreases colocalization of BACE1 and beta APP, which reduces beta-cleavage of beta APP. Therefore, the data demonstrate that Dx-E represents a novel A beta-reducing process which could have fewer side effects than secretase inhibitors. Copyright (C) 2009 S. Karger AG, Base
<Abstract of Published Report>Differences among Three Sister Strains of NON/Shi Mice in Sensitivity to Urinary Tract Carcinogenesis by N-Butyl-N-(4-hydroxybutyl)nitrosamine.
Efferent projections from the preoptic area for thermoregulatory skin vasomotor response
Effects of estrogen on thermoregulatory tail vasomotion and heat-escape behavior in freely moving female rats
<Abstract of Published Report>Differences among Three Sister Strains of NON/Shi Mice in Sensitivity to Urinary Tract Carcinogenesis by N-Butyl-N-(4-hydroxybutyl)nitrosamine.
Conformational Restriction Approach to β‑Secretase (BACE1) Inhibitors: Effect of a Cyclopropane Ring To Induce an Alternative Binding Mode
Improvement of a drug’s binding activity using
the conformational
restriction approach with sp<sup>3</sup> hybridized carbon is becoming
a key strategy in drug discovery. We applied this approach to BACE1
inhibitors and designed four stereoisomeric cyclopropane compounds
in which the ethylene linker of a known amidine-type inhibitor <b>2</b> was replaced with chiral cyclopropane rings. The synthesis
and biologic evaluation of these compounds revealed that the <i>cis</i>-(1<i>S</i>,2<i>R</i>) isomer <b>6</b> exhibited the most potent BACE1 inhibitory activity among
them. X-ray structure analysis of the complex of <b>6</b> and
BACE1 revealed that its unique binding mode is due to the apparent
CH−π interaction between the rigid cyclopropane ring
and the Tyr71 side chain. A derivatization study using <b>6</b> as a lead molecule led to the development of highly potent inhibitors
in which the structure–activity relationship as well as the
binding mode of the compounds clearly differ from those of known amidine-type
inhibitors