Abstract

1. FXIa-6f is a high affinity, orally bioavailable macrocyclic FXIa inhibitor with antithrombotic activity in preclinical species.

2. The objectives of this study were to characterize the in vitro metabolism, determine circulating metabolites in pre-clinical species, and examine the disposition of the compound in a bile duct-cannulated rat study (BDC) study to inform clinical development of the compound and the medicinal chemistry approach to identify molecules with improved properties.

3. Across species, metabolic pathways included several oxidative metabolites, including hydroxylated metabolites on the macrocycle or P1 region, descarbamoylation of the methyl carbamate side chain, and a glutathione conjugate on the 2,6-difluoro-3-chlorophenyl ring.

4. In BDC rat, the absorbed dose of [³H]FXIa-6f was cleared mainly by metabolism, with excretion of drug-related material in the bile, mostly as metabolites.

5. In all preclinical species, the parent drug was the primary drug-related component in circulation, but the species differences in the metabolic pathways observed in vitro were reflected in the plasma, where M6, a descarbamoylated metabolite, was more prominent in rat plasma, and M9, a hydroxylated metabolite, was more prominent in monkey plasma. Based on the available data, the human metabolism appears to be most similar to monkey.

摘要

1. FXIa-6f 是一种高亲和力、口服生物可利用的大环 FXIa 抑制剂，在临床前物种中具有抗血栓形成活性。

2. 本研究的目的是表征体外代谢，确定临床前物种的循环代谢物，并检查化合物在胆管插管大鼠研究 (BDC) 研究中的分布，以告知化合物的临床开发和药物化学方法来识别具有改进特性的分子。

3. 在整个物种中，代谢途径包括几种氧化代谢物，包括大环或 P1 区域上的羟基化代谢物、氨基甲酸甲酯侧链的脱氨甲酰化以及 2,6-二氟-3-氯苯环上的谷胱甘肽偶联物。

4. 在 BDC 大鼠中，[ ³ H]FXIa-6f的吸收剂量主要通过代谢清除，药物相关物质在胆汁中排泄，主要作为代谢物。

5. 在所有临床前物种中，母体药物是循环中主要的药物相关成分，但体外观察到的代谢途径的物种差异反映在血浆中，其中 M6，一种去氨甲酰化代谢物，在大鼠血浆中更为突出，并且M9 是一种羟基化代谢物，在猴血浆中更为突出。根据现有数据，人类的新陈代谢似乎与猴子最相似。