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.

中文翻译：

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新型嘧啶衍生物作为骨合成代谢剂通过 BMP2/SMAD1 信号通路促进成骨的设计、合成和生物学评价

双膦酸盐等抗再吸收抑制剂被广泛使用，但其疗效有限且副作用严重。虽然皮下注射特立帕肽[PTH (1-34)]是一种有效的合成代谢疗法，但不建议长期重复皮下注射。今后，口服生物可利用的基于小分子的新型疗法是改善治疗的未满足的医疗需求。在这项研究中，我们设计、合成了 31 种嘧啶衍生物作为有效的骨合成代谢剂，并对其进行了生物学评价。一系列体外实验证实N- (5-溴-4-(4-溴苯基)-6-(2,4,5-三甲氧基苯基)嘧啶-2-基)己酰胺 ( 18a ) 是最有效的合成代谢剂下午 1 点。它通过激活 BMP2/SMAD1 信号通路上调成骨基因（RUNX2 和 1 型 col）的表达来促进成骨。使用体内骨折缺陷模型进一步验证了体外成骨潜力，其中化合物18a在5 mg kg ^-1下促进骨形成速率。我们还建立了18a的构效关系和药代动力学研究。