Study on drug synthesis and activity of sodium olpadronate

doi:10.5246/jcps.2022.11.075

Abstract

Abstract:

As a systemic metabolic disease caused by a variety of factors, osteoporosis is characterized by reduced bone mass, bone tissue microstructural degradation, and decreased bone mechanical properties, accompanied by bone fragility and fracture, which is a common risk of senile disease. In China, osteoporosis has become a common disease and has frequent morbidity, with the incidence trend on the rise. Bisphosphates have received much attention in this field as inhibitory bone resorption agents, and sodium olpadronate belongs to the third-generation bisphosphonates. This experiment investigated the synthetic process and pharmacological activity of sodium olpadronate. Using 3-(N,N-dimethylamino)-propionitrile as the starting material, the synthesis process was improved to reduce cost with a total yield of 49.7%, which was 24.0% higher than that reported in the literature. Pharmacodynamic experiments showed that sodium olpadronate could be used to treat osteoporosis. Moreover, toxicology experiments showed no obvious toxic side effects. Taken together, sodium olpadronate had very promising development prospects.

Key words: Opraedronate, Osteoporosis, Bisphosphonate, Synthesis process, Pharmacodynamics, Toxicology

Supporting:

Yuehua Liu, Zhangqin Xue, Jianming Wei, Ruomeng Wei, Baodong Yin, Aiqin Liu. Study on drug synthesis and activity of sodium olpadronate[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(11): 883-892.

Figures/Tables 7

Table 1. Effect of sodium olpadronate on the body weight of rats with osteoporosis caused by retinoic acid (g, x ± SD).

Table 2. Effects of sodium olpadronate on ALP, Ca, and P of rats with osteoporosis caused by retinoic acid (x ± SD, n = 10).

Table 3. Effects of sodium olpadronate on bone biomechanics of rats with osteoporosis caused by retinoic acid (x ± SD).

Table 4. Effects of sodium olpadronate on femoral calcium content and trabecular area of rats with osteoporosis caused by retinoic acid (x ± SD).

Table 5. Effect of sodium olpadronate on the body weight of mice.

References 27

[1]	Letarouilly, J.G.; Broux, O.; Clabaut, A. New insights into the epigenetics of osteoporosis. Genomics. 2019, 111, 793–798.
[2]	Cauley, J.A. Public health impact of osteoporosis. J. Gerontol. A Biol. Sci. Med. Sci. 2013, 68, 1243–1251.
[3]	Baron, R.; Ferrari, S.; Russell, R.G.G. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011, 48, 677–692.
[4]	McClung, M.; Harris, S.T.; Miller, P.D.; Bauer, D.C.; Davison, K.S.; Dian, L.; Hanley, D.A.; Kendler, D.L.; Yuen, C.K.; Lewiecki, E.M. Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am. J. Med. 2013, 126, 13–20.
[5]	Ebetino, F.H.; Hogan, A.M.L.; Sun, S.T.; Tsoumpra, M.K.; Duan, X.C.; Triffitt, J.T.; Kwaasi, A.A.; Dunford, J.E.; Barnett, B.L.; Oppermann, U.; Lundy, M.W.; Boyde, A.; Kashemirov, B.A.; McKenna, C.E.; Russell, R.G.G. The relationship between the chemistry and biological activity of the bisphosphonates. Bone. 2011, 49, 20–33.
[6]	Yavropoulou, M.P.; Makras, P.; Anastasilakis, A.D. Bazedoxifene for the treatment of osteoporosis. Expert Opin. Pharmacother. 2019, 20, 1201–1210.
[7]	Martinkovich, S.; Shah, D.; Planey, S.L.; Arnott, J.A. Selective estrogen receptor modulators: tissue specificity and clinical utility. Clin. Interv. Aging. 2014, 9, 1437–1452.
[8]	Hadji, P. The evolution of selective estrogen receptor modulators in osteoporosis therapy. Climacteric. 2012, 15, 513–523.
[9]	Bock, O.; Felsenberg, D. Bisphosphonates in the management of postmenopausal osteoporosis: optimizing efficacy in clinical practice. Clin. Interv. Aging. 2008, 3, 279–297.
[10]	Russell, R.G.G. Bisphosphonates: the first 40 years. Bone. 2011, 49, 2–19.
[11]	Sun, M.; Iqbal, J.; Singh, S.; Sun, L.; Zaidi, M. The crossover of bisphosphonates to cancer therapy. Ann. NY Acad. Sci. 2010, 1211, 107–112.
[12]	Coleman, R.; Body, J.J.; Aapro, M.; Hadji, P.; Herrstedt, J. Bone health in cancer patients: ESMO Clinical Practice Guidelines. Ann. Oncol. 2014, 25, iii124–iii137.
[13]	Rogers, M.J.; Frith, J.C.; Luckman, S.P.; Coxon, F.P.; Benford, H.L.; M̈onkk̈onen, J.; Auriola, S.; Chilton, K.M.; Russell, R.G.G. Molecular mechanisms of action of bisphosphonates. Bone. 1999, 24, 73S–79S.
[14]	Ansari, N.; Sims, N.A. The cells of bone and their interactions. Handb. Exp. Pharmacol. 2020, 262, 1–25.
[15]	Hirabayashi, H.; Fujisaki, J. Bone-specific drug delivery systems: approaches via chemical modification of bone-seeking agents. Clin. Pharmacokinet. 2003, 42, 1319–1330.
[16]	Buffo, L.; Rossini, M.; Buoncristiano, A.; Girardello, S.; Zamberlan, N.; Diani, F.; Adami, S. I bisfosfonati: un'alternativa al trattamento estrogenico nell'osteoporosi postmenopausale. Esperienza con alendronato [Diphosphonates: and alternative to estrogen therapy in postmenopausal osteoporosis. Experience with alendronate. Minerva. Ginecol. 1996, 48, 263–272.
[17]	Chen, L.R.; Ko, N.Y.; Chen, K.H. Medical treatment for osteoporosis: from molecular to clinical opinions. Int. J. Mol. Sci. 2019, 20, 2213.
[18]	Anesi, Generali, Sandoni, Pozzi, Grande. From osteoclast differentiation to osteonecrosis of the jaw: molecular and clinical insights. Int. J. Mol. Sci. 2019, 20, 4925.
[19]	Rogers, M.J.; Mönkkönen, J.; Munoz, M.A. Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton. Bone. 2020, 139, 115493.
[20]	Zameer, S.; Najmi, A.K.; Vohora, D.; Akhtar, M. Bisphosphonates: Future perspective for neurological disorders. Pharmacol. Rep. 2018, 70, 900–907.
[21]	Wahl, O.; Holzgrabe, U. Impurity profiling of ibandronate sodium by HPLC-CAD. J. Pharm. Biomed. Anal. 2015, 114, 254–264.
[22]	Schoener, C.A.; Curtis-Fisk, J.L.; Rogers, T.L.; Tate, M.P. High throughput research and evaporation rate modeling for solvent screening for ethylcellulose barrier membranes in pharmaceutical applications. Drug Dev. Ind. Pharm. 2016, 42, 1700–1707.
[23]	Nazari, M.; Davoodabadi, A.; Huang, D.Z.; Luo, T.F.; Ghasemi, H. On interfacial viscosity in nanochannels. Nanoscale. 2020, 12, 14626–14635.
[24]	PK, R.; Sankaran, B.P. Tay-Sachs disease. 2020 nov 17. in: StatPearls [Internet]. treasure island (FL): StatPearls publishing; 2021 jan-. PMID: 33232090. 2020. 11.
[25]	Figueroa, I.A.; Coates, J.D. Microbial phosphite oxidation and its potential role in the global phosphorus and carbon cycles. Adv. Appl. Microbiol. 2017, 98, 93–117.
[26]	Wang, X.D.; Liang, T.Z.; Zhu, Y.X.; Qiu, J.C.; Qiu, X.J.; Lian, C.J.; Gao, B.; Peng, Y.; Liang, A.J.; Zhou, H.; Yang, X.M.; Liao, Z.H.; Li, Y.Y.; Xu, C.X.; Su, P.Q.; Huang, D.S. Melatonin prevents bone destruction in mice with retinoic acid-induced osteoporosis. Mol. Med. Camb. Mass. 2019, 25, 43.
[27]	Oršolić, N.; Nemrava, J.; Jeleč, Ž.; Kukolj, M.; Odeh, D.; Terzić, S.; Fureš, R.; Bagatin, T.; Bagatin, D. The beneficial effect of proanthocyanidins and icariin on biochemical markers of bone turnover in rats. Int. J. Mol. Sci. 2018, 19, 2746.