The discovery of SB-435495. A potent, orally active inhibitor of lipoprotein-associated phospholipase A(2) for evaluation in man.
The introduction of a functionalised amido substituent into a series of 1-(biphenylmethylacetamido)-pyrimidones has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency and very encouraging developability properties. Diethylaminoethyl derivative 32, SB-435495, was selected for progression to man.
Blackie
Josie A
JA
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, SG1 2NY, Stevenage, UK.
Bloomer
Jackie C
JC
Brown
Murray J B
MJ
Cheng
Hung-Yuan
HY
Elliott
Richard L
RL
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
Whittaker
Caroline M
CM
D000284:Administration, Oral; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011744:Pyrimidinones / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D008074:Lipoproteins; D011744:Pyrimidinones; C470971:SB-435495; D010741:Phospholipases A