ABSTRACT
Potent 3-anilino-4-arylmaleimide glycogen synthase kinase-3 (GSK-3) inhibitors have been prepared using automated array methodology. A number of these are highly selective, having little inhibitory potency against more than 20 other protein kinases.
Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Maleimides/pharmacology , Animals , Bipolar Disorder/drug therapy , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Glycogen Synthase Kinases , Humans , Maleimides/chemical synthesis , Maleimides/chemistry , Maleimides/therapeutic use , Molecular Structure , Structure-Activity RelationshipABSTRACT
Starting from two weakly active hits from high throughput screening, a novel series of 2-(alkylthio)-pyrimidin-4-ones with high potency and selectivity for lipoprotein-associated phospholipase A2 has been designed. In contrast to previously known inhibitors, these have been shown to act by a non-covalent and substrate competitive mechanism.
Subject(s)
Phospholipases A/antagonists & inhibitors , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , 1-Alkyl-2-acetylglycerophosphocholine Esterase , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Phospholipases A2 , Pyrimidinones/chemical synthesis , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Aryl hydroxylamine derivatives have been synthesised that are some of the most potent inhibitors of hCMV protease prepared to date (IC50 14-60 nM). Mass spectrometry studies indicate that oxazinone derived hydroxylamines inhibit the enzyme by acylation of Ser132 whereas non-oxazinone derived hydroxylamines appear to inhibit via formation of a sulfinanilide at Cys138.
Subject(s)
Anti-Infective Agents/chemical synthesis , Cytomegalovirus/enzymology , Hydroxylamines/chemical synthesis , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Amino Acid Sequence , Anti-Infective Agents/pharmacology , Binding Sites , Cytomegalovirus Infections , Humans , Hydroxylamines/pharmacology , Mass Spectrometry , Molecular Sequence Data , Molecular Structure , Peptide Fragments/chemistry , Serine Proteinase Inhibitors/pharmacology , TrypsinABSTRACT
ATP-citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Inhibitors of the enzyme represent a potentially novel class of hypolipidemic agent, which are anticipated to have combined hypocholesterolemic and hypotriglyceridemic properties. A series of 2-substituted butanedioic acids have been designed and synthesized as inhibitors of the enzyme. The best compounds, 58, 68, 71, 74 have reversible Ki's in the 1-3 microM range against the isolated rat enzyme. As representative of this compound class, 58, has been shown to exert its inhibitory action through a mainly competitive mechanism with respect to citrate and a noncompetitive one with respect to CoA. None of the inhibitors were able to inhibit cholesterol and/or fatty acid synthesis in HepG2 cells. This has been attributed to the adverse physicochemical properties of the molecules leading to a lack of cell penetration. Despite this, a lead structural class of compound has been identified with the potential for modification into potent, cell-penetrant, and efficacious inhibitors of ATP-citrate lyase.
