Oxygenated analogues of UK-396082 as inhibitors of activated thrombin activatable fibrinolysis inhibitor.

Abstract

A suitable inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa) has the potential to be a novel treatment for thrombosis. The TAFIa inhibitor UK-396082 (1) was used as a starting point to seek more potent analogues. With knowledge of encouraging human pharmacokinetics and toleration for the clinical candidate (1), the programme continued to seek structure-activity relationships (SAR) that could positively impact on both potency and half-life, and therefore the projected dose of any future nominated clinical agent. A series of oxygenated analogues based on compound 1 were prepared to evaluate changes in pharmacology, selectivity and pharmacokinetics.

• Authors: Dafydd R Owen, David J Bull, Mark E Bunnage, Melanie S Glossop, Robert J Maguire, Ross S Strang
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 20 Issue 1 Pg. 92-6 (Jan 01 2010) ISSN: 1464-3405 [Electronic] England
• PMID: 19954973 (Publication Type: Journal Article)
• Copyright: Copyright 2009 Elsevier Ltd. All rights reserved.

Chemical References

• 5-amino-2-((1-n-propyl-1H-imidazol-4-yl)methyl)pentanoic acid
• Amino Acids
• Fibrinolytic Agents
• Imidazoles
• Protease Inhibitors
• Carboxypeptidase B2
• Oxygen

Topics

• Administration, Oral
• Amino Acids (chemical synthesis, chemistry, pharmacokinetics)
• Animals
• Carboxypeptidase B2 (antagonists & inhibitors, metabolism)
• Fibrinolytic Agents (chemical synthesis, chemistry, pharmacokinetics)
• Half-Life
• Humans
• Imidazoles (chemical synthesis, chemistry, pharmacokinetics)
• Oxygen (chemistry)
• Protease Inhibitors (chemical synthesis, chemistry, pharmacokinetics)
• Rats
• Structure-Activity Relationship