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.
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, SG1 2NY, Stevenage, UK.
Josie A
JA
Blackie
Jackie C
JC
Bloomer
Murray J B
MJ
Brown
Hung-Yuan
HY
Cheng
Richard L
RL
Elliott
Beverley
B
Hammond
Deirdre M B
DM
Hickey
Robert J
RJ
Ife
Colin A
CA
Leach
V Ann
VA
Lewis
Colin H
CH
Macphee
Kevin J
KJ
Milliner
Kitty E
KE
Moores
Ivan L
IL
Pinto
Stephen A
SA
Smith
Ian G
IG
Stansfield
Steven J
SJ
Stanway
Maxine A
MA
Taylor
Colin J
CJ
Theobald
Caroline M
CM
Whittaker
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