2-(Alkylthio)pyrimidin-4-ones as novel, reversible inhibitors of lipoprotein-associated phospholipase A2.
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.
Boyd
H F
HF
SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK.
Flynn
S T
ST
Hickey
D M
DM
Ife
R J
RJ
Jones
M
M
Leach
C A
CA
Macphee
C H
CH
Milliner
K J
KJ
Rawlings
D A
DA
Slingsby
B P
BP
Smith
S A
SA
Stansfield
I G
IG
Tew
D G
DG
Theobald
C J
CJ
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D010741:Phospholipases A; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase