Exploring the chemical space of gamma-secretase modulators.
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.
Zettl
Heiko
H
ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland.
Weggen
Sascha
S
Schneider
Petra
P
Schneider
Gisbert
G
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D017076:Computer-Aided Design; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008954:Models, Biological; D015394:Molecular Structure; D017711:Nonlinear Dynamics
D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases