Design,Synthesis And Biological Evaluation Of P38α Protein Kinase Inhibitors And V-ATPase Inhibitors As Anti-osteoporosis Compounds

Osteoporosis is a functional disease caused by imbalance between osteoblast and osteoclast. The bone continuously lost causes bones to become loose and fragile. With the arrival of an aging population, osteoporosis becomes a worldwide health problem. Osteoporosis and diabetes, with Alzheimer’s disease was listed as the world’s three major age-related diseases.Excessive absorption of osteoclasts to bone is the direct cause of the onset of osteoporosis. Along with the growth of the age, the supplement of the bone becomes extremely difficult, how to inhibit osteoclast bone resorption become a hot research. At present, the inhibition of osteoclast differentiation and osteoclast resorption lacunae acidification on bone becomes an important strategy for development of new drugs to the therapeutic of bone disease caused by osteoclast.p38MAPK signaling pathway is one of the most important signal pathway in osteoclast differentiation and maturation process, so the search for specific p38a protein kinase inhibitors has become the anti-osteoporosis drug R&D hotspot. This paper takes SCIO469as the leading compound, aided by computer molecular flexible docking, were designed and synthesized133compounds, some compounds have been screened. Screening results showed that the introduction of sterically hindered hydrophobic substituents on the compounds can obtain better biological activity. The further evaluation of the biological activity on several performance of the compound in the preliminary screening. These screening including osteoclast differentiation and proliferation, osteoclastic bone resorption of osteoclasts, expression of specific genes, signal pathways in osteoclast differentiation and proliferation. Further screening of these compounds showed good activity and no obvious cytotoxic effect on other cells within the effective concentration range.The flexible docking results of the corresponding compounds with p38a protein kinase indicate that these designed moleculars can produce strong hydrogen bonds with the amino acid residues Gly110and Met109. These compouds can also produce strong van der Waals force with the amino acid residue Tyr35. Large hydrophobic substituents can be closely integrated with the latter part of the hydrophobic pocket, and some of these compounds can produce strong hydrogen bonds with guard residues Thr106to further stabilize the conformation of compounds in the ATP-binding pocket. Based on these results, we optimize the structure of compounds synthesized by next, hope can get the better biological activity.Pyrimidine structure is widely present in biologically active compounds, there are also pyrimidine structure exists in some p38a protein kinase inhibitors. In this paper, we present a simple and straightforward reaction to provide the polysubstituted5-aminopyrimidine-2(1H)-thiones from vinyl azides. Hope hat the parent nucleus can be applied to the development of novel p38a inhibitors. Through the flexible docking of polysubstituted5-aminopyrimidine-2(1H)-thione with p38α protein kinase we can find such structure can produce hydrogen bonds with the ATP-binding pocket, and modification of functional groups in the corresponding sites can further strengthen the interaction with the ATP-binding pocket.V-ATPase enzyme is an ATP-dependent proton pump V-ATPase enzyme involved in the regulation of the pH value of the human body environment, especially plays a very importantrole in the acidification of the resorption lacunae of osteoclasts resorption process. Thus, inhibition of V-ATPase enzyme activity can effectively block the process of osteoclast bone resorption.Based on the leading compound SB242784, we used a chemical structure similar design to synthesiz a class of benzimidazole derivatives. Meanwhile, according to the characteristics of osteoporosis, we designed a targeted screening process, including cytotoxicity, inhibition of acidification, proton transport, the V-ATPase enzyme hydrolysis, osteoclast formation and bone resorptionaspects. Biological screening of such compounds are still in progress.