Potent, orally active inhibitors of lipoprotein-associated phospholipase A(2): 1-(biphenylmethylamidoalkyl)-pyrimidones.
A series of 1-(biphenylmethylamidoalkyl)-pyrimidones has been designed as nanomolar inhibitors of recombinant lipoprotein-associated phospholipase A(2) with high potency in whole human plasma. 5-(Pyrazolylmethyl) derivative 16 and 5-(methoxypyrimidinylmethyl) derivative 27 demonstrated excellent pharmacodynamic profiles which correlated well with their pharmacokinetic effects.
Boyd
Helen F
HF
GlaxoSmithKline, Medicines Research Centre, Gunnell's Wood Road, SG1 2NY, Stevenage, UK.
Fell
Stephen C M
SC
Hickey
Deirdre M B
DM
Ife
Robert J
RJ
Leach
Colin A
CA
Macphee
Colin H
CH
Milliner
Kevin J
KJ
Pinto
Ivan L
IL
Rawlings
D Anthony
DA
Smith
Stephen A
SA
Stansfield
Ian G
IG
Stanway
Steven J
SJ
Theobald
Colin J
CJ
Whittaker
Caroline M
CM
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000284:Administration, Oral; D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D011817:Rabbits; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase