Design, synthesis and biological evaluation of novel pyrimidine derivatives as bone anabolic agents promoting osteogenesis via the BMP2/SMAD1 signaling pathway
This journal is © The Royal Society of Chemistry..
Anti-resorptive inhibitors such as bisphosphonates are widely used but they have limited efficacy and serious side effects. Though subcutaneous injection of teriparatide [PTH (1-34)] is an effective anabolic therapy, long-term repeated subcutaneous administration is not recommended. Henceforth, orally bio-available small-molecule-based novel therapeutics are unmet medical needs to improve the treatment. In this study, we designed, synthesized, and carried out a biological evaluation of 31 pyrimidine derivatives as potent bone anabolic agents. A series of in vitro experiments confirmed N-(5-bromo-4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-yl)hexanamide (18a) as the most efficacious anabolic agent at 1 pM. It promoted osteogenesis by upregulating the expression of osteogenic genes (RUNX2 and type 1 col) via activation of the BMP2/SMAD1 signaling pathway. In vitro osteogenic potential was further validated using an in vivo fracture defect model where compound 18a promoted the bone formation rate at 5 mg kg-1. We also established the structure-activity relationship and pharmacokinetic studies of 18a.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
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| Enthalten in: |
RSC medicinal chemistry - 15(2024), 2 vom: 21. Feb., Seite 677-694 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rastogi, Sumit K [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 24.02.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1039/d3md00500c |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368798712 |
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| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a This journal is © The Royal Society of Chemistry. | ||
| 520 | |a Anti-resorptive inhibitors such as bisphosphonates are widely used but they have limited efficacy and serious side effects. Though subcutaneous injection of teriparatide [PTH (1-34)] is an effective anabolic therapy, long-term repeated subcutaneous administration is not recommended. Henceforth, orally bio-available small-molecule-based novel therapeutics are unmet medical needs to improve the treatment. In this study, we designed, synthesized, and carried out a biological evaluation of 31 pyrimidine derivatives as potent bone anabolic agents. A series of in vitro experiments confirmed N-(5-bromo-4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-yl)hexanamide (18a) as the most efficacious anabolic agent at 1 pM. It promoted osteogenesis by upregulating the expression of osteogenic genes (RUNX2 and type 1 col) via activation of the BMP2/SMAD1 signaling pathway. In vitro osteogenic potential was further validated using an in vivo fracture defect model where compound 18a promoted the bone formation rate at 5 mg kg-1. We also established the structure-activity relationship and pharmacokinetic studies of 18a | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Khanka, Sonu |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Santosh |e verfasserin |4 aut | |
| 700 | 1 | |a Lakra, Amardeep |e verfasserin |4 aut | |
| 700 | 1 | |a Rathur, Rajat |e verfasserin |4 aut | |
| 700 | 1 | |a Sharma, Kriti |e verfasserin |4 aut | |
| 700 | 1 | |a Bisen, Amol Chhatrapati |e verfasserin |4 aut | |
| 700 | 1 | |a Bhatta, Rabi Sankar |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Ravindra |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Divya |e verfasserin |4 aut | |
| 700 | 1 | |a Sinha, Arun K |e verfasserin |4 aut | |
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