Ando Masafumi, Kawai Shota, Morishita Ko, Takashima Shunsuke, Otake Kazuya, Yamamoto Megumi, Shoji Yoshimichi, Hinoi Eiichi, Kitao Tatsuya, Shirahase Hiroaki
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.
Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University.
Chem Pharm Bull (Tokyo). 2025;73(1):25-38. doi: 10.1248/cpb.c24-00664.
Osteoporosis is caused by an imbalance between bone resorption and formation, which decreases bone mass and strength and increases the risk of fracture. Therefore, osteoporosis is treated with oral resorption inhibitors, such as bisphosphonates, and parenteral osteogenic drugs, including parathyroid hormone and antisclerostin antibodies. However, orally active osteogenic drugs have not yet been developed. In the present study, to find novel candidates for oral osteogenic drugs, various benzofuran derivatives were synthesized and their effects on osteoblast differentiation were examined in mouse mesenchymal stem cells (ST2 cells). Among the compounds tested, 3-{4-[2-(2-isopropoxyethoxy)ethoxy]phenyl}benzofuran-5-carboxamide (23d) exhibited potent osteoblast differentiation-promoting activity, estimated as EC for increasing alkaline phosphatase activity, and good oral absorption in female rats, resulting in high C/EC. Dual-energy X-ray absorptiometry scanning revealed that 23d at 10 mg/kg/d for 8 weeks increased femoral bone mineral density in ovariectomized rats with an elevation in plasma bone-type alkaline phosphatase activity, and micro-computed tomography showed that it increased bone volume, mineral contents, and strength in femoral diaphysis cortical, but not trabecular bone during the experiment period. 23d potently inhibited cyclin-dependent kinase 8 (CDK8) activity, suggesting that its osteoblastogenic activity is mediated by the suppression of CDK8, as previously reported for diphenylether derivatives. In conclusion, the structure-activity relationships of novel benzofuran derivatives were clarified and 3,5-disubstituted benzofuran was identified as a useful scaffold for orally active osteogenic compounds. Compound 23d exhibited potent osteoblastogenic activity through CDK8 inhibition and osteogenic effects in ovariectomized rats, indicating its potential as an orally active anti-osteoporotic drug.
骨质疏松症是由骨吸收与骨形成之间的失衡引起的，这种失衡会降低骨量和骨强度，并增加骨折风险。因此，骨质疏松症的治疗采用口服吸收抑制剂，如双膦酸盐，以及肠外成骨药物，包括甲状旁腺激素和抗硬化蛋白抗体。然而，口服活性成骨药物尚未开发出来。在本研究中，为了寻找口服成骨药物的新候选物，合成了各种苯并呋喃衍生物，并在小鼠间充质干细胞（ST2细胞）中检测了它们对成骨细胞分化的影响。在所测试的化合物中，3-{4-[2-(2-异丙氧基乙氧基)乙氧基]苯基}苯并呋喃-5-甲酰胺（23d）表现出强大的促进成骨细胞分化活性，以增加碱性磷酸酶活性的半数有效浓度（EC）来估计，并且在雌性大鼠中具有良好的口服吸收，从而导致高的血药浓度与半数有效浓度比值（C/EC）。双能X线吸收法扫描显示，23d以10mg/kg/d的剂量给药8周，可增加去卵巢大鼠的股骨骨矿物质密度，并提高血浆骨型碱性磷酸酶活性，微计算机断层扫描显示，在实验期间，它增加了股骨干皮质骨的骨体积、矿物质含量和强度，但对小梁骨没有影响。23d强烈抑制细胞周期蛋白依赖性激酶8（CDK8）的活性，这表明其成骨细胞生成活性是通过抑制CDK8介导的，正如先前对二苯醚衍生物的报道。总之，阐明了新型苯并呋喃衍生物的构效关系，并确定3,5-二取代苯并呋喃是口服活性成骨化合物的有用骨架。化合物23d通过抑制CDK8表现出强大的成骨细胞生成活性，并在去卵巢大鼠中具有成骨作用，表明其作为口服活性抗骨质疏松药物的潜力。
