奥帕膦酸钠的药物合成及活性研究

doi:10.5246/jcps.2022.11.075

中国药学(英文版) ›› 2022, Vol. 31 ›› Issue (11): 883-892.DOI: 10.5246/jcps.2022.11.075

奥帕膦酸钠的药物合成及活性研究

刘玥华^#, 薛章勤^#, 魏剑明, 魏若梦, 殷宝栋, 刘爱芹^*()

山东第一医科大学山东省医学科学院材料研究所, 山东济南 250062

收稿日期:2022-01-11 修回日期:2022-04-26 接受日期:2022-05-09 出版日期:2022-11-30 发布日期:2022-11-30
通讯作者: 刘爱芹
作者简介:
+ Tel.: +86-18815314707, E-mail: liuaiqin6@126.com

Study on drug synthesis and activity of sodium olpadronate

Yuehua Liu^#, Zhangqin Xue^#, Jianming Wei, Ruomeng Wei, Baodong Yin, Aiqin Liu^*()

Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250062, Shandong, China

Received:2022-01-11 Revised:2022-04-26 Accepted:2022-05-09 Online:2022-11-30 Published:2022-11-30
Contact: Aiqin Liu
About author:
# Yuehua Liu and Zhangqin Xue contributed equally to this work.

摘要/Abstract

摘要：

骨质疏松症是多种病因引起的一种全身代谢性疾病, 以骨量减少、骨组织微观结构退化和骨的力学性能下降为特征, 伴随着骨脆性和骨折风险的增加, 是一种常见的老年性疾病。在中国, 骨质疏松症已成常见病、多发病, 发病率呈上升趋势。双磷酸盐作为抑制骨吸收药物在这一领域受到广泛关注, 奥帕膦酸钠属于第三代双膦酸盐。本实验研究了奥帕膦酸钠的合成工艺和药理活性。以3-(N,N-二甲氨基)-丙腈为起始原料, 对合成工艺进行了改进, 降低了成本, 反应总收率为49.7%, 比文献报道提高了24.0%。药效学实验表明奥帕膦酸钠对骨质疏松症具有明显的治疗作用; 毒理学实验显示其无明显的毒副作用。奥帕膦酸钠具有很好的开发前景。

关键词: 奥帕膦酸钠, 骨质疏松症, 双膦酸盐, 合成工艺, 药效学, 毒理学

Abstract:

As a systemic metabolic disease caused by a variety of factors, osteoporosis is characterized by reduced bone mass, bone tissue microstructural degradation, and decreased bone mechanical properties, accompanied by bone fragility and fracture, which is a common risk of senile disease. In China, osteoporosis has become a common disease and has frequent morbidity, with the incidence trend on the rise. Bisphosphates have received much attention in this field as inhibitory bone resorption agents, and sodium olpadronate belongs to the third-generation bisphosphonates. This experiment investigated the synthetic process and pharmacological activity of sodium olpadronate. Using 3-(N,N-dimethylamino)-propionitrile as the starting material, the synthesis process was improved to reduce cost with a total yield of 49.7%, which was 24.0% higher than that reported in the literature. Pharmacodynamic experiments showed that sodium olpadronate could be used to treat osteoporosis. Moreover, toxicology experiments showed no obvious toxic side effects. Taken together, sodium olpadronate had very promising development prospects.

Key words: Opraedronate, Osteoporosis, Bisphosphonate, Synthesis process, Pharmacodynamics, Toxicology

Supporting:

刘玥华, 薛章勤, 魏剑明, 魏若梦, 殷宝栋, 刘爱芹. 奥帕膦酸钠的药物合成及活性研究[J]. 中国药学(英文版), 2022, 31(11): 883-892.

Yuehua Liu, Zhangqin Xue, Jianming Wei, Ruomeng Wei, Baodong Yin, Aiqin Liu. Study on drug synthesis and activity of sodium olpadronate[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(11): 883-892.

图/表 7

Scheme 1. Synthetic route of olpadronate sodium.

Table 1. Effect of sodium olpadronate on the body weight of rats with osteoporosis caused by retinoic acid (g, x ± SD).

Figure 1. A. Normal control group (×200); B. Model group (×200); C. Positive control group (×200); D. High dose group (×200); E. Medium dose group (×200); F. Low dose group (×200).

Table 2. Effects of sodium olpadronate on ALP, Ca, and P of rats with osteoporosis caused by retinoic acid (x ± SD, n = 10).

Table 3. Effects of sodium olpadronate on bone biomechanics of rats with osteoporosis caused by retinoic acid (x ± SD).

Table 4. Effects of sodium olpadronate on femoral calcium content and trabecular area of rats with osteoporosis caused by retinoic acid (x ± SD).

Table 5. Effect of sodium olpadronate on the body weight of mice.

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奥帕膦酸钠的药物合成及活性研究

Study on drug synthesis and activity of sodium olpadronate

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