Discovery of Novel Antiosteoporosis Leads with Bone Resorption Inhibition and Anabolic Promotion through a Chemotype-Assembly Approach.
J Med Chem
; 67(17): 15311-15327, 2024 Sep 12.
Article
em En
| MEDLINE
| ID: mdl-39167391
ABSTRACT
Developing a dual-efficiency agent with antiresorptive and anabolic applications is a promising strategy for treating osteoporosis. This study reports the discovery of dual antiosteoporosis agents via a chemotype-assembly approach. Chemotype analysis identified 12 antiresorptive and 12 anabolic chemotypes and 7 dual-function chemotype-assembly rules. Based on these assembly rules, a dual-functional compound S24 was discovered. S24 exhibits osteoclastogenesis inhibition with an IC50 value of 10.28 µM and osteoblast differentiation stimulation at 10 µM. S24 derivatives were designed and synthesized based on the activity relationship of the chemotypes. This yielded a more active compound, S24-14, with an osteoclastogenesis inhibition IC50 value of 0.40 µM and osteoblast differentiation stimulation at 1.0 µM; compound S24-14 also suppressed bone loss in vivo. These results prove that S24-14 can be a potential lead for antiosteoporosis drug development.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteoblastos
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Osteogênese
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Osteoporose
/
Reabsorção Óssea
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Anabolizantes
Limite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
Estados Unidos