ABSTRACT
The development of a novel series of piperazinyl pyrimidines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a screening hit provided a series of potent gamma-secretase modulators with >180-fold in vitro selectivity over inhibition of Notch cleavage.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Piperazines/chemistry , Pyrimidines/chemistry , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/physiology , Cell Line, Tumor , HeLa Cells , Humans , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Piperazines/pharmacology , Pyrimidines/pharmacologyABSTRACT
A series of 3-aryl-4-hydroxyquinolin-2(1H)-ones with fatty acid synthase inhibitory activity was prepared. Starting from a derivative with an IC(50) = 1.4 microM, SAR studies led to compounds with more than 70-fold increase in potency (IC(50) < 20 nM).
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Fatty Acid Synthases/antagonists & inhibitors , Hydroxyquinolines/chemistry , Hydroxyquinolines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Animals , Enzyme Inhibitors/chemistry , Fatty Acid Synthases/metabolism , Humans , Hydroxyquinolines/chemical synthesis , Malonates/chemistry , Microwaves , Molecular Structure , Quinolines/chemical synthesis , Rats , Structure-Activity RelationshipABSTRACT
Catalytic asymmetric cross-coupling reactions between aldehydes and N-acylimines have been discovered that employ thiazolylalanine derivatives as catalysts. Alkylation of the thiazolyl moiety, followed by in situ generation of the derived thiazolium ylide using a tertiary amine base, leads to the active catalyst. alpha-Amidoketone products are isolated in up to 90% yield with up to 87% enantiomeric excess (>98% ee after a single recrystallization). The use of a hindered base to suppress product racemization was stimulated by a mechanistic study that revealed an isotope effect on the racemization rate of the product.
