ABSTRACT
The 3,4-fused sulfamides, sulfonamides and sulfone have been identified as highly potent gamma-secretase inhibitors. Evaluation of the SAR of substitution within these series has allowed the identification of a range of compounds which significantly reduce brain A beta in transgenic mouse models and thus have potential as possible treatments for Alzheimer's disease.
Subject(s)
Endopeptidases/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Sulfones/chemistry , Sulfones/pharmacology , Amyloid Precursor Protein Secretases , Animals , Aspartic Acid Endopeptidases , Crystallography, X-Ray , Cyclization , Models, Molecular , Molecular Structure , Protease Inhibitors/chemistry , Rats , Structure-Activity Relationship , Sulfones/chemical synthesisABSTRACT
A series of novel 4,4-disubstituted cyclohexylamine based NK(1) antagonists is described. The effect of changes to the C(1)-C(4) relative stereochemistry on the cyclohexane ring and replacements for the flexible linker are discussed, leading to the identification of compounds with high affinity and good in vivo duration of action.
Subject(s)
Cyclohexylamines/chemical synthesis , Cyclohexylamines/pharmacology , Neurokinin-1 Receptor Antagonists , Animals , Binding Sites , CHO Cells , Central Nervous System/drug effects , Central Nervous System/metabolism , Cricetinae , Cyclohexylamines/pharmacokinetics , Gerbillinae , Inhibitory Concentration 50 , Molecular Conformation , Radioligand Assay , Receptors, Neurokinin-1/chemistry , Structure-Activity RelationshipABSTRACT
A series of novel 4,4-disubstituted cyclohexylamines as NK(1) receptor antagonists is described: modifications to the amine moiety retain NK(1) receptor binding affinity whilst disrupting I(Kr) affinity.
