R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Bioorg Med Chem Lett. 2021 Dec 15;54:128440. doi: 10.1016/j.bmcl.2021.128440. Epub 2021 Nov 3.
The continuing investigation of SAR of 3-aminothieno[2,3-b]pyridine-2-carboxamide derivatives has been described. In this study, C4-piperidine derivatives with polar functional groups were synthesized to develop orally available bone anabolic agents. The optimized compound 9o (DS96432529), which exhibited the best PK profile and high in vitro activity, showed the highest in vivo efficacy in this series. Moreover, significant synergistic effects were observed following co-administration of DS96432529 and alendronate or parathyroid hormone. The mechanism of action is most likely mediated through CDK8 inhibition.
对 3-氨基噻吩并[2,3-b]吡啶-2-甲酰胺衍生物的 SAR 研究仍在继续。在这项研究中，我们合成了具有极性官能团的 C4-哌啶衍生物，以开发可口服的骨合成代谢药物。优化后的化合物 9o（DS96432529）具有最佳的 PK 特征和高体外活性，在该系列中表现出最高的体内疗效。此外，DS96432529 与阿伦膦酸盐或甲状旁腺激素联合用药时观察到显著的协同作用。其作用机制很可能是通过 CDK8 抑制介导的。
