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

Keiji Saito; Tsuyoshi Shinozuka; Akira Nakao; Tomonori Kunikata; Daisuke Nakai; Yoko Nagai; Satoru Naito

doi:10.1016/j.bmcl.2021.128440

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.

Authors

Keiji Saito¹, Tsuyoshi Shinozuka², Akira Nakao², Tomonori Kunikata², Daisuke Nakai², Yoko Nagai², Satoru Naito²

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.

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