Jaiswal Arvind Kumar, Raj Anuj, Kushawaha Ajay Kishor, Maji Bhaskar, Bhatt Hemlata, Verma Shikha, Katiyar Sarita, Ansari Alisha, Bisen Amol Chhatrapati, Tripathi Arsh, Siddiqi Mohammad Imran, Bhatta Rabi Sankar, Trivedi Ritu, Sashidhara Koneni V
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India; Division of Endocrinology, CSIR-Central Drug Research Institute, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
Bioorg Chem. 2025 Apr;157:108216. doi: 10.1016/j.bioorg.2025.108216. Epub 2025 Jan 28.
This study explores a series of twenty-four newly synthesized pyrzole-dihydropyrimidinone hybrids as potential bone anabolic agents. Initially, an alkaline phosphatase assay, a common marker of bone formation, was used to screen all compounds for their ability to stimulate osteogenic potential. Initial screening identified three promising candidates (5f, 5u and 5w) that were subsequently confirmed to be non-toxic to osteoblasts. Further investigation revealed that compound 5w displayed the most potent osteoanabolic effect, promoting osteoblast differentiation and upregulating mRNAs expression of osteogenic gene. Based on the promising in vitro and in vivo activity, structure-activity relationship (SAR) analysis revealed a furan ring on the dihydropyrimidinone unit and electron-donating groups on the N-phenyl ring of the pyrazole moiety to be crucial for osteogenic activity. Additionally, molecular docking, favorable pharmacokinetic properties and In silico ADME predictions suggest potential oral bioavailability. These findings establish the pyrazole-dihydropyrimidinone scaffold as a promising hit for developing a new class of orally active bone anabolic agents.
本研究探索了一系列24种新合成的吡唑-二氢嘧啶酮杂合物作为潜在的骨合成代谢剂。最初，使用碱性磷酸酶测定法（一种常见的骨形成标志物）来筛选所有化合物刺激成骨潜能的能力。初步筛选确定了三种有前景的候选物（5f、5u和5w），随后证实它们对成骨细胞无毒。进一步研究表明，化合物5w表现出最有效的骨合成代谢作用，促进成骨细胞分化并上调成骨基因的mRNA表达。基于有前景的体外和体内活性，构效关系（SAR）分析表明，二氢嘧啶酮单元上的呋喃环和吡唑部分的N-苯基环上的供电子基团对成骨活性至关重要。此外，分子对接、良好的药代动力学性质和计算机辅助ADME预测表明其具有潜在的口服生物利用度。这些发现确立了吡唑-二氢嘧啶酮支架作为开发新型口服活性骨合成代谢剂的有前景的靶点。
