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. Epub 2021 Nov 3.

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.

MeSH terms

  • Administration, Oral
  • Anabolic Agents / administration & dosage
  • Anabolic Agents / chemistry
  • Anabolic Agents / pharmacology*
  • Bone and Bones / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Anabolic Agents