The discovery of SB-435495. A potent, orally active inhibitor of lipoprotein-associated phospholipase A(2) for evaluation in man

Josie A Blackie; Jackie C Bloomer; Murray J B Brown; Hung-Yuan Cheng; Richard L Elliott; Beverley Hammond; Deirdre M B Hickey; Robert J Ife; Colin A Leach; V Ann Lewis; Colin H Macphee; Kevin J Milliner; Kitty E Moores; Ivan L Pinto; Stephen A Smith; Ian G Stansfield; Steven J Stanway; Maxine A Taylor; Colin J Theobald; Caroline M Whittaker

doi:10.1016/s0960-894x(02)00473-0

The discovery of SB-435495. A potent, orally active inhibitor of lipoprotein-associated phospholipase A(2) for evaluation in man

Bioorg Med Chem Lett. 2002 Sep 16;12(18):2603-6. doi: 10.1016/s0960-894x(02)00473-0.

Affiliation

¹ GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, SG1 2NY, Stevenage, UK.

PMID: 12182870
DOI: 10.1016/s0960-894x(02)00473-0

Abstract

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.

MeSH terms

Administration, Oral
Animals
Biphenyl Compounds / administration & dosage
Biphenyl Compounds / chemistry
Biphenyl Compounds / metabolism
Biphenyl Compounds / pharmacology*
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Humans
Lipoproteins / metabolism*
Phospholipases A / antagonists & inhibitors*
Phospholipases A / metabolism
Pyrimidinones / administration & dosage
Pyrimidinones / chemistry
Pyrimidinones / metabolism
Pyrimidinones / pharmacology*
Rabbits
Structure-Activity Relationship

Substances

Biphenyl Compounds
Enzyme Inhibitors
Lipoproteins
Pyrimidinones
SB-435495
Phospholipases A