The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2.
Modification of the pyrimidone 5-substituent in clinical candidate SB-435495 has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency. Cyclopentyl fused derivative 21, SB-480848, showed an enhanced in vitro and in vivo profile versus SB-435495 and has been selected for progression to man.
Blackie
Josie A
JA
Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
Bloomer
Jackie C
JC
Brown
Murray J B
MJ
Cheng
Hung Yuan
HY
Hammond
Beverley
B
Hickey
Deirdre M B
DM
Ife
Robert J
RJ
Leach
Colin A
CA
Lewis
V Ann
VA
Macphee
Colin H
CH
Milliner
Kevin J
KJ
Moores
Kitty E
KE
Pinto
Ivan L
IL
Smith
Stephen A
SA
Stansfield
Ian G
IG
Stanway
Steven J
SJ
Taylor
Maxine A
MA
Theobald
Colin J
CJ
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000097:blood; D054467:Phospholipases A2; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D001713:Biphenyl Compounds; D004048:Diethylamines; D013440:Sulfides
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D010741:Phospholipases A; D054467:Phospholipases A2; D011744:Pyrimidinones; D011994:Recombinant Proteins; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D013440:Sulfides