Oxygenated analogues of UK-396082 as inhibitors of activated thrombin activatable fibrinolysis inhibitor.
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.
Owen
Dafydd R
DR
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich CT13 9NJ, UK. dafydd.owen@pfizer.com
Bull
David J
DJ
Bunnage
Mark E
ME
Glossop
Melanie S
MS
Maguire
Robert J
RJ
Strang
Ross S
RS
D000284:Administration, Oral; D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D010100:Oxygen / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
C526817:5-amino-2-((1-n-propyl-1H-imidazol-4-yl)methyl)pentanoic acid; D000596:Amino Acids; D005343:Fibrinolytic Agents; D007093:Imidazoles; D011480:Protease Inhibitors; D025901:Carboxypeptidase B2; D010100:Oxygen