Institute of Chemical Technology and Engineering, Poznań University of Technology, Berdychowo 4, 60-965, Poznań, Poland.
Faculty of Chemistry, Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wrocław, Poland.
Pharmacol Rep. 2024 Oct;76(5):1160-1173. doi: 10.1007/s43440-024-00624-2. Epub 2024 Jul 15.
The study aimed to evaluate the therapeutic potential of fourteen newly synthesized bisphosphonates by assessing their bioavailability, bone affinity, and cytotoxicity. These bisphosphonates included a series of aminomethylenebisphosphonates and standard compounds such as risedronate and tiludronate.
Drug permeability was determined using Parallel Artificial Membrane Permeability Assays (PAMPA), while bone affinity was assessed by sorption on hydroxyapatite. Bacterial cell response to the bisphosphonates was also examined using Lactobacillus paracasei cells as a model.
Several tested compounds, including BP3 to BP8 and BP11, which feature substituents in the pyridine ring such as methyl groups, iodine, bromine, chlorine, or hydroxyl groups, demonstrated potentially more beneficial therapeutic properties than commercially used bisphosphonates. These compounds showed stronger bone affinity and higher gastrointestinal absorption with comparable or lower cytotoxic effects. Specifically, BP11 exhibited the highest bone affinity, while BP8 and BP11 showed the greatest permeability.
The findings suggest that BP3 BP8, and BP11 are promising candidates for further research. These results highlight the importance of comprehensively evaluating bisphosphonates' therapeutic properties to identify effective treatments for osteoporosis and other bone diseases.
本研究旨在评估 14 种新合成的双膦酸盐的治疗潜力，方法是评估它们的生物利用度、骨亲和力和细胞毒性。这些双膦酸盐包括一系列亚氨基二甲基双膦酸盐和标准化合物，如利塞膦酸盐和替鲁膦酸盐。
使用平行人工膜渗透测定法（PAMPA）测定药物通透性，通过在羟磷灰石上吸附评估骨亲和力。还使用副干酪乳杆菌细胞作为模型，研究了双膦酸盐对细菌细胞的反应。
包括 BP3 至 BP8 和 BP11 在内的几种测试化合物，其吡啶环上的取代基为甲基、碘、溴、氯或羟基，与商业上使用的双膦酸盐相比，具有潜在更有益的治疗特性。这些化合物表现出更强的骨亲和力和更高的胃肠道吸收，同时具有相似或更低的细胞毒性。具体来说，BP11 表现出最高的骨亲和力，而 BP8 和 BP11 表现出最大的通透性。
这些发现表明 BP3、BP8 和 BP11 是进一步研究的有前途的候选药物。这些结果强调了全面评估双膦酸盐治疗特性的重要性，以确定治疗骨质疏松症和其他骨疾病的有效方法。
