Exploring the chemical space of gamma-secretase modulators

Heiko Zettl; Sascha Weggen; Petra Schneider; Gisbert Schneider

doi:10.1016/j.tips.2010.05.007

Exploring the chemical space of gamma-secretase modulators

Trends Pharmacol Sci. 2010 Sep;31(9):402-10. doi: 10.1016/j.tips.2010.05.007. Epub 2010 Jun 28.

Authors

Heiko Zettl¹, Sascha Weggen, Petra Schneider, Gisbert Schneider

Affiliation

¹ ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland.

PMID: 20591508
DOI: 10.1016/j.tips.2010.05.007

Abstract

gamma-Secretase is a key enzyme in the pathophysiology of Alzheimer's disease (AD) and is responsible for the production of potentially toxic amyloid-beta (Abeta) 42 peptides. gamma-Secretase modulators (GSMs) are small molecules (<600 Da) causing a product shift from Abeta42 toward shorter and less toxic Abeta fragments. Classical non-steroidal anti-inflammatory drugs (NSAIDs) constituted the first class of GSMs, and therefore many of today's GSMs exhibit NSAID-like overall structure combining an acidic head group with a lipophilic backbone. Recent developments include structurally different non-acidic GSMs. Here we summarize common structural features of GSMs, pick up the controversial discussion regarding their mechanism of action, and show how computational analysis of pharmacophoric features can help reveal their pharmacological profile.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Computer-Aided Design*
Drug Design
Drug Evaluation, Preclinical / methods*
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Models, Biological
Molecular Structure
Nonlinear Dynamics

Substances

Enzyme Inhibitors
Amyloid Precursor Protein Secretases