N-1 substituted pyrimidin-4-ones: novel, orally active inhibitors of lipoprotein-associated phospholipase A2.
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.
Boyd
H F
HF
SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK.
Fell
S C
SC
Flynn
S T
ST
Hickey
D M
DM
Ife
R J
RJ
Leach
C A
CA
Macphee
C H
CH
Milliner
K J
KJ
Moores
K E
KE
Pinto
I L
IL
Porter
R A
RA
Rawlings
D A
DA
Smith
S A
SA
Stansfield
I G
IG
Tew
D G
DG
Theobald
C J
CJ
Whittaker
C M
CM
D000284:Administration, Oral; D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008074:Lipoproteins / Q000378:metabolism*; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054467:Phospholipases A2; D011744:Pyrimidinones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits
D004791:Enzyme Inhibitors; D008074:Lipoproteins; D011744:Pyrimidinones; D010741:Phospholipases A; D054467:Phospholipases A2