ABSTRACT
The lipophilic 1-substituent in a series of 1-((amidolinked)-alkyl)-pyrimidones, inhibitors of recombinant lipoprotein-associated phospholipase A(2), has been modified to give inhibitors of high potency in human plasma and enhanced physicochemical properties. Phenylpiperazineacetamide derivative 23 shows very promising oral activity.
Subject(s)
Enzyme Inhibitors/pharmacology , Phospholipases A/antagonists & inhibitors , Phospholipases A/blood , 1-Alkyl-2-acetylglycerophosphocholine Esterase , Administration, Oral , Animals , Enzyme Inhibitors/chemical synthesis , Humans , Inhibitory Concentration 50 , Metabolic Clearance Rate/physiology , Microsomes, Liver/metabolism , Piperazines/chemical synthesis , Piperazines/pharmacology , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Rabbits , RatsABSTRACT
Modification of the pyrimidone 5-substituent in a series of 1-((amidolinked)-alkyl)-pyrimidones, lipophilic inhibitors of lipoprotein-associated phospholipase A2, has given inhibitors of nanomolar potency and improved physicochemical properties. Compound 23 was identified as a potent, highly water soluble. CNS penetrant inhibitor suitable for intravenous administration.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Phospholipases A/antagonists & inhibitors , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Animals , Arteriosclerosis/drug therapy , Drug Administration Routes , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Humans , Male , Molecular Structure , Phospholipases A/metabolism , Phospholipases A2 , Pyrimidinones/chemical synthesis , Rabbits , Rats , Solubility , Water/chemistryABSTRACT
From two related series of 2-(alkylthio)-pyrimidones, a novel series of 1-((amidolinked)-alkyl)-pyrimidones has been designed as nanomolar inhibitors of human lipoprotein-associated phospholipase A2. These compounds show greatly enhanced activity in isolated plasma. Selected derivatives such as compounds 51 and 52 are orally active with a good duration of action.
Subject(s)
Enzyme Inhibitors/pharmacology , Lipoproteins/metabolism , Phospholipases A/antagonists & inhibitors , Pyrimidinones/pharmacology , Administration, Oral , Animals , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Molecular Structure , Phospholipases A/metabolism , Phospholipases A2 , Pyrimidinones/administration & dosage , Pyrimidinones/chemistry , RabbitsABSTRACT
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.