Discovery of 3-amino-4-{(3S)-3-[(2-ethoxyethoxy)methyl]piperidin-1-yl}thieno[2,3-b]pyridine-2-carboxamide (DS96432529): A potent and orally active bone anabolic agent,Bioorganic & Medicinal Chemistry Letters

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Discovery of 3-amino-4-{(3S)-3-[(2-ethoxyethoxy)methyl]piperidin-1-yl}thieno[2,3-b]pyridine-2-carboxamide (DS96432529): A potent and orally active bone anabolic agent
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2021-11-03 , DOI: 10.1016/j.bmcl.2021.128440
Keiji Saito ₁ , Tsuyoshi Shinozuka ₁ , Akira Nakao ₁ , Tomonori Kunikata ₁ , Daisuke Nakai ₁ , Yoko Nagai ₁ , Satoru Naito ₁

Affiliation

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.

中文翻译：

发现 3-amino-4-{(3S)-3-[(2-ethoxyethoxy)methyl]piperidin-1-yl}thieno[2,3-b]pyridine-2-carboxamide (DS96432529)：一种有效的口服药物活性骨合成代谢剂

已经描述了对 3-氨基噻吩并[2,3- b ]吡啶-2-甲酰胺衍生物的 SAR 的持续研究。在这项研究中，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剂。优化后的化合物9o (DS96432529) 表现出最佳的 PK 曲线和高体外活性，在该系列中显示出最高的体内功效。此外，在 DS96432529 和阿仑膦酸盐或甲状旁腺激素共同给药后观察到显着的协同作用。作用机制很可能是通过 CDK8 抑制介导的。

更新日期：2021-11-16

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