新穎吡唑衍生物應用於治療骨質疏鬆之潛力

Abstract

隨著人類壽命的延長，老化相關之疾病的發生將更加普遍，如 : 骨質疏鬆症。目前骨質疏鬆症相關治療藥物仍有無法承受的副作用，以及療效不佳的問題，在現今的治療中，我們仍需要有效的新穎治療藥物，因此，我們設計合成出一系列之吡唑衍生物，更進一步測試這些衍生物在骨質疏鬆症相關活體外與活體內實驗之效力。最佳的衍生物為化合物13，其具有二甲氨基乙基之結構，化合物13能有效抑制活體外破骨細胞生成與蝕骨活性，化合物13對於蝕骨細胞生成之前期的抑制功效優於後期。在骨質疏鬆動物模式卵巢切除母鼠中，可以發現化合物13可以有效地抑制總骨小樑體積、骨小樑數量及骨小樑厚度的降低，另一方面，化合物13也可以拮抗卵巢切除母鼠血清中的蝕骨指標與造骨指標的上升。綜上，化合物13具有發展為治療骨質疏鬆症之新穎藥物之潛力。

As human beings live longer, age-related diseases such as osteoporosis will become more prevalent. Intolerant side effects and poor responses to current treatments are observed. Therefore, novel effective therapeutic agents are greatly needed. Here, pyrazole derivatives were designed and synthesized, and their osteoclastogenesis inhibitory effects both in vitro and in vivo were evaluated. The most promising compound 13 with a 2- (dimethylamino)ethyl group inhibited markedly in vitro osteoclastogenesis as well as the bone resorption activity of osteoclasts. Compound 13 affected osteoclast’s early proliferation and differentiation more than later fusion and maturation stages. In ovariectomized (OVX) mice, compound 13 can inhibit the loss of trabecular bone volume, trabecular bone number, and trabecular thickness. Moreover, compound 13 can antagonize OVX-induced reduction of serum bone resorption marker and then compensatory increase of the bone formation marker. To sum up, compound 13 has high potential to be developed into a novel therapeutic agent for treating osteoporosis in the future.