The identification of a potent, water soluble inhibitor of lipoprotein-associated phospholipase A2.
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.
GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK.
H F
HF
Boyd
B
B
Hammond
D M
DM
Hickey
R J
RJ
Ife
C A
CA
Leach
V A
VA
Lewis
C H
CH
Macphee
K J
KJ
Milliner
I L
IL
Pinto
S A
SA
Smith
I G
IG
Stansfield
C J
CJ
Theobald
C M
CM
Whittaker
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy; D004333:Drug Administration Routes; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054467:Phospholipases A2; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D012995:Solubility; D014867:Water / Q000737:chemistry
D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D014867:Water; D010741:Phospholipases A; D054467:Phospholipases A2