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

  • Bioorg Med Chem Lett. 2021 Dec 15;54:128440. doi: 10.1016/j.bmcl.2021.128440.
Keiji Saito  1 ,  Tsuyoshi Shinozuka  2 ,  Akira Nakao  2 ,  Tomonori Kunikata  2 ,  Daisuke Nakai  2 ,  Yoko Nagai  2 ,  Satoru Naito  2
Affiliations
  • 1. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
  • 2. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 34742889 DOI: 10.1016/j.bmcl.2021.128440
Abstract

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.

Keywords
ALPase enhancer; Bone anabolic agents; CDK8; Fsp(3); Osteoporosis; Synergistic effects; Thieno[2,3-b]pyridine.
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