Potent, orally active inhibitors of lipoprotein-associated phospholipase A(2): 1-(biphenylmethylamidoalkyl)-pyrimidones

Helen F Boyd; Stephen C M Fell; Deirdre M B Hickey; Robert J Ife; Colin A Leach; Colin H Macphee; Kevin J Milliner; Ivan L Pinto; D Anthony Rawlings; Stephen A Smith; Ian G Stansfield; Steven J Stanway; Colin J Theobald; Caroline M Whittaker

doi:10.1016/s0960-894x(01)00678-3

Potent, orally active inhibitors of lipoprotein-associated phospholipase A(2): 1-(biphenylmethylamidoalkyl)-pyrimidones

Bioorg Med Chem Lett. 2002 Jan 7;12(1):51-5. doi: 10.1016/s0960-894x(01)00678-3.

Authors

Helen F Boyd¹, Stephen C M Fell, Deirdre M B Hickey, Robert J Ife, Colin A Leach, Colin H Macphee, Kevin J Milliner, Ivan L Pinto, D Anthony Rawlings, Stephen A Smith, Ian G Stansfield, Steven J Stanway, Colin J Theobald, Caroline M Whittaker

Affiliation

¹ GlaxoSmithKline, Medicines Research Centre, Gunnell's Wood Road, SG1 2NY, Stevenage, UK.

PMID: 11738571
DOI: 10.1016/s0960-894x(01)00678-3

Abstract

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.

MeSH terms

1-Alkyl-2-acetylglycerophosphocholine Esterase
Administration, Oral
Animals
Drug Design
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacokinetics
Humans
Inhibitory Concentration 50
Kinetics
Phospholipases A / antagonists & inhibitors*
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry
Pyrimidinones / pharmacokinetics*
Rabbits
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Pyrimidinones
Phospholipases A
1-Alkyl-2-acetylglycerophosphocholine Esterase