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Synthesis and biological activities of drugs for the treatment of osteoporosis

Zhou S1Huang G2Chen G3.

Eur J Med Chem. 2020 Apr 19;197:112313. doi: 10.1016/j.ejmech.2020.112313. [Epub ahead of print]



Osteoporosis is an asymptomatic progressive disease. With the improvement of people’s living standard and the aging of population, osteoporosis and its fracture have become one of the main diseases threatening the aging society. The serious medical and social burden caused by this has aroused wide public concern. Osteoporosis is listed as one of the three major diseases of the elderly. At present, the drugs for osteoporosis include bone resorption inhibitors and bone formation promoters. The purpose of these anti-osteoporosis drugs is to balance osteoblast bone formation and osteoclast bone resorption. With the development of anti-osteoporosis drugs, new anti osteoporosis drugs have been designed and synthesized. There are many kinds of new compounds with anti osteoporosis activity, but most of them are concentrated on the original drugs with anti osteoporosis activity, or the natural products with anti-osteoporosis activity are extracted from the natural products for structural modification to obtain the corresponding derivatives or analogues. These target compounds showed good ALP activity in vitro and in vivo, promoted osteoblast differentiation and mineralization, or had anti TRAP activity, inhibited osteoclast absorption. This work attempts to systematically review the studies on the synthesis and bioactivity of anti-osteoporosis drugs in the past 10 years. The structure-activity relationship was discussed, which provided a reasonable idea for the design and development of new anti-osteoporosis drugs.

. Conclusion and prospect

Osteoporosis is a group of bone diseases caused by various causes and has been widely prevalent around the world. The biggest harm of osteoporosis to human body is fracture. With the growth of age, the aggravation of aging population, the risk of fracture increases gradually. Osteoporosis will bring a lot of harm to the patients, for the patients themselves will bring a certain amount of pain, but also will bring the necessary economic burden to the family. Osteoporosis has brought serious burden to human society in the world health system. It is very necessary to research and develop new anti-osteoporosis drugs with high activity for the treatment of osteoporosis. Osteoporosis occurs because of the imbalance between osteoblastic bone formation and osteoclast bone resorption, and anti-osteoporosis drugs were used to adjust this imbalance. Drugs currently used in the treatment of osteoporosis include bone resorption inhibitors and bone formation promoters. The drugs that inhibit bone resorption mainly act on osteoclasts, inhibit the differentiation and maturation of osteoclasts, and reduce bone resorption. Drugs to promote bone formation mainly act on osteoblasts and activate their bone formation functions. In recent years, a large number of anti-osteoporosis drugs have been designed and synthesized. These novel compounds were basically derivatives or analogues of existing drugs or natural products that have anti-osteoporosis properties as lead compounds, using basic drug design principles. These target compounds showed excellent enhancement of ALP activity in vitro or in vivo, promoted osteoblast differentiation and mineralization, or had anti-TRAP activity, and inhibited osteoclast absorption. This review covers the recent advances of anti-osteoporosis drugs (2009-2019), including 1-(benzo [b] thiophen-2-yl) ethanone analogues, 3-amino-2-hydroxypropoxyisoflavone derivatives, indirubin-3′-oxime derivatives, lipophilic alendronate derivatives, bicyclic substituted hydroxyphenylmethanones, 3, 4-diarylbenzopyran based amide derivatives, rhein amides, coumarin-imidazo[1, 2-a] pyridine derivatives, dihydrobenzofuran cyclopropane carboxylic acid, dalbergin analogues, purple acid phosphatase inhibitors, 4-alkoxy-thieno[2,3-b] pyridine derivatives. Among the 12 types of target compounds with different chemical structures, according to their mechanism of action against osteoporosis, they could be divided into bone resorption inhibitors and bone formation promoters.Some of these designed target compounds exhibit excellent anti-osteoporosis activity and may be used as candidate drugs for follow-up studies or as the lead compounds for further structural modification. Compound208was in 1 PM when it had ALP activity, the compound 277 could restrain the targets of the osteoporosis caused by CaSR of IC50 was 7.45 nM, the compound 305 in a significant bone protection, the compound 225 had obvious inhibitory effect to TRAP activity and the inhibition rate was 98%, and the compound 260 inhibition activity of TRAP IC50was 1 μM. The anti-osteoporosis activity of these target compounds were generally at the μM or nM level. The development of new drugs was a long process, which takes about more than tento decades years.At present, the research stage of these novel anti-osteoporosis compounds is still in vitro screening or in vivo activity evaluation.Most of the targeted compounds have not been toxicologically, pharmacokinetically studied or in the preparation stage.Therefore, these compounds still have a long way to go before they can be truly used as anti-osteoporosis drugs.These novel structural compounds were reported to offer hope for the treatment of osteoporosis. The structure-activity relationships (SAR) was also discussed, and abundant SAR paves the way for the further rational develop of new anti-osteoporosis drugs.At the same time, we also hope that more anti-osteoporosis compounds will be reported, so that people can screen out the drugs with the best activity and the lowest toxic and side effects for clinical treatment.