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
| Autor: | Tomonori Kunikata, Satoru Naito, Tsuyoshi Shinozuka, Akira Nakao, Daisuke Nakai, Yoko Nagai, Keiji Saito |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Anabolism
medicine.drug_class Stereochemistry Clinical Biochemistry Administration Oral Pharmaceutical Science Parathyroid hormone Carboxamide Biochemistry Bone and Bones Anabolic Agents Structure-Activity Relationship chemistry.chemical_compound In vivo Drug Discovery Pyridine medicine Humans Molecular Biology Dose-Response Relationship Drug Molecular Structure Organic Chemistry In vitro Mechanism of action chemistry Molecular Medicine medicine.symptom |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 54:128440 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2021.128440 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect