Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich CT13 9NJ, UK.
Bioorg Med Chem Lett. 2010 Jan 1;20(1):92-6. doi: 10.1016/j.bmcl.2009.11.029. Epub 2009 Nov 13.
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.
一种合适的活化血栓调节蛋白激活纤溶抑制物（TAFIa）抑制剂具有成为新型血栓治疗药物的潜力。TAFIa 抑制剂 UK-396082（1）被用作寻找更有效类似物的起点。由于了解了临床候选物（1）在人体药代动力学和耐受性方面的良好表现，该项目继续寻求能够积极影响效力和半衰期的结构活性关系（SAR），从而影响任何未来指定临床药物的剂量。基于化合物 1，我们制备了一系列含氧类似物来评估其在药理学、选择性和药代动力学方面的变化。
