Research and Development, Bayer AG, Pharmaceuticals, 42103 Wuppertal, Germany.
Research and Development, Bayer AG, Pharmaceuticals, 13342 Berlin, Germany.
J Med Chem. 2020 Nov 12;63(21):12574-12594. doi: 10.1021/acs.jmedchem.0c01035. Epub 2020 Oct 27.
Despite extensive research on small molecule thrombin inhibitors for oral application in the past decades, only a single double prodrug with very modest oral bioavailability has reached human therapy as a marketed drug. We have undertaken major efforts to identify neutral, non-prodrug inhibitors. Using a holistic analysis of all available internal data, we were able to build computational models and apply these for the selection of a lead series with the highest possibility of achieving oral bioavailability. In our design, we relied on protein structure knowledge to address potency and identified a small window of favorable physicochemical properties to balance absorption and metabolic stability. Protein structure information on the pregnane X receptor helped in overcoming a persistent cytochrome P450 3A4 induction problem. The selected compound series was optimized to a highly potent, neutral, non-prodrug thrombin inhibitor by designing, synthesizing, and testing derivatives. The resulting optimized compound, BAY1217224, has reached first clinical trials, which have confirmed the desired pharmacokinetic properties.
尽管过去几十年中对小分子凝血酶抑制剂的口服应用进行了广泛的研究，但仅有一种双前药以非常有限的口服生物利用度作为市售药物进入人体治疗。我们已经做出了重大努力来确定中性、非前药抑制剂。我们使用对所有可用内部数据的整体分析，能够构建计算模型并将其应用于选择具有最高可能实现口服生物利用度的先导系列。在我们的设计中，我们依赖于蛋白质结构知识来解决效力问题，并确定了一个有利于吸收和代谢稳定性平衡的有利物理化学性质的小窗口。妊娠相关 X 受体的蛋白质结构信息有助于克服持续的细胞色素 P450 3A4 诱导问题。通过设计、合成和测试衍生物，对所选化合物系列进行优化，得到了一种高效、中性、非前药凝血酶抑制剂。所得到的优化化合物 BAY1217224 已进入首次临床试验，该试验证实了所需的药代动力学特性。
