The bone morphogenetic protein (BMP) pathway is a promising new target for the design of therapeutic agents for the treatment of low bone mass. This study optimized the structure of the anti-osteoporosis compound 38 by balancing its lipophilicity and improving its stability. Twenty derivatives which were not reported in the literature were designed and synthesized. The ovariectomized rat model of osteoporosis was selected to evaluate the therapeutic effects. Compound 125 showed better therapeutic efficacy than that of 38. We verified the anti-osteoporosis activity and BMP-2 protein upregulation after treatment with 125 in a zebrafish osteoporosis model. We found that 125 improved the ADME properties, therapeutic efficacy, and pharmacokinetics of the drug. Overall, we evaluated the anti-osteoporosis effects of the compounds of this type, preliminarily determined the target patient population, verified the mechanism of action, clarified the level of toxicity, and provided preliminary ADME data. We believe that these compounds can both correct bone loss that is already occurring in patients and have broad clinical applicability.

骨形态发生蛋白（BMP）途径是设计低骨量治疗剂的有希望的新目标。这项研究通过平衡亲脂性和改善稳定性来优化抗骨质疏松化合物38的结构。设计并合成了文献中未报道的二十种衍生物。选择卵巢切除的骨质疏松大鼠模型以评估治疗效果。化合物125显示出比38更好的疗效。我们验证了在斑马鱼骨质疏松症模型中用125治疗后的抗骨质疏松活性和BMP-2蛋白上调。我们发现125改善了药物的ADME特性，治疗功效和药代动力学。总体而言，我们评估了这类化合物的抗骨质疏松作用，初步确定了目标患者人群，验证了作用机制，阐明了毒性水平，并提供了初步的ADME数据。我们相信这些化合物既可以纠正患者已经发生的骨质流失，又具有广泛的临床适用性。