Pfizer Global Research and Development, Chesterfield, MO 63017, USA.
Bioorg Med Chem Lett. 2010 Dec 1;20(23):7164-8. doi: 10.1016/j.bmcl.2010.07.059. Epub 2010 Jul 23.
In this manuscript, we report the discovery of the substituted 2-trifluoromethyl-2H-benzopyran-3-carboxylic acids as a novel series of potent and selective cyclooxygenase-2 (COX-2) inhibitors. We provide the structure-activity relationships, optimization of design, testing criteria, and human half-life data. The challenge of a surprisingly long half-life (t(1/2)=360 h) of the first clinical candidate 1 and human t(1/2) had been difficult to predict based on allometric scaling for this class of highly ppb compounds. We used a microdose strategy which led to the discovery of clinical agents 18c-(S), 29b-(S), and 34b-(S) with human half-life of 57, 13, and 11 h.
在本手稿中，我们报告了取代的 2-三氟甲基-2H-苯并吡喃-3-羧酸作为一类新型强效和选择性环氧化酶-2（COX-2）抑制剂的发现。我们提供了结构-活性关系、设计优化、测试标准和人体半衰期数据。第一个临床候选物 1 的半衰期（t(1/2)=360 h）出乎意料地长，这给我们带来了挑战，而根据同类高 ppb 化合物的比例预测，人类 t(1/2)很难预测。我们使用了一种微剂量策略，从而发现了具有 57、13 和 11 h 人体半衰期的临床候选物 18c-(S)、29b-(S)和 34b-(S)。
