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1.
Bioorg Med Chem Lett ; 11(14): 1925-9, 2001 Jul 23.
Article in English | MEDLINE | ID: mdl-11459662

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 , Rats
2.
Bioorg Med Chem Lett ; 10(22): 2557-61, 2000 Nov 20.
Article in English | MEDLINE | ID: mdl-11086729

ABSTRACT

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 , Rabbits
3.
Bioorg Med Chem Lett ; 10(4): 395-8, 2000 Feb 21.
Article in English | MEDLINE | ID: mdl-10714508

ABSTRACT

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 Specificity
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