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Synthesis and Preclinical Pharmacology of 2-(2-Aminopyrimidinio) Ethylidene-1,1-Bisphosphonic Acid Betaine (ISA-13-1)-A Novel Bisphosphonate

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Abstract

Purpose. To validate our hypothesis that a bisphosphonate (BP) having a nitrogen-containing heterocyclic ring on the side chain, and with no hydroxyl on the geminal carbon would possess increased activity, and better oral bioavailability due to enhanced solubility of its calcium complexes/salts and weaker Ca chelating properties.

Methods. A novel BP, 2-(2-aminopyrimidinio)ethylidene-l,l-bisphosphonic acid betaine (ISA-13-1) was synthesized. The physicochemical properties and permeability were studied in vitro. The effects on macrophages, bone resorption (young growing rat model), and tumor-induced osteolysis (Walker carcinosarcoma) were studied in comparison to clinically used BPs.

Results. The solubility of the Ca salt of ISA-13-1 was higher, and the log βCa: BP stability constant and the affinity to hydroxyapatite were lower than those of alendronate and pamidronate. ISA-13-1 exhibited effects similar to those of alendronate on bone volume, on bone osteolysis, and on macrophages, following delivery by liposomes. ISA-13-1 was shown to have 1.5−1.7 times better oral absorption than the other BPs with no deleterious effects on the tight junctions of intestinal tissue.

Conclusions. The similar potency to clinically used BPs, the increased oral absorption as well as the lack of effect on tissue tight junction of ISA-13-1 warrant its further consideration as a potential drug for bone diseases.

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REFERENCES

  1. H. Fleisch. Bisphosphonates in bone disease: From the laboratory to the patient, The Parthenon Publishing Group, NY, 1997.

    Google Scholar 

  2. N. Makkonen, M. R. Hirvonen, T. Teravainen, K. Savolainen, and J. Monkkonen. Different effects of three bisphosphonates on nitric oxide production by RAW 264 macrophage-like cells in vitro. J. Pharmacol. Exp. Ther. 277:1097-1102 (1996).

    Google Scholar 

  3. G. A. Rodan. Mechanisms of action of bisphosphonates. Annu. Rev. Pharmacol. Toxicol. 38:375-388 (1998).

    Google Scholar 

  4. J. H. Lin. Bisphosphonates: A review of their pharmacokinetic properties. Bone 18:75-85 (1996).

    Google Scholar 

  5. P. C. D. Groen, et al. Esophagitis associated with the use of alendronate. New Engl. J. Med. 335:1016-1021 (1996).

    Google Scholar 

  6. J. H. Lin, I.-W. Chen, and F. A. Deluna. On the absorption of alendronate in rats. J. Pharm. Sci. 83:1741-1746 (1994).

    Google Scholar 

  7. I. M. Twiss, R. de Water, J. den Hartigh, R. Sparidans, W. Ramp-Koopmanschap, H. Brill, M. Wijdeveld, and P. Vermeij. Cytotoxic effects of Pamidronate on monolayers of human intestinal epithelial (Caco-2) cells and its epithelial transport. J. Pharm. Sci. 83:699-703 (1994).

    Google Scholar 

  8. W. K. Sietsema and F. H. Ebetino. Bisphophonates in development for metabolic bone disease. Exp. Opin. Invest. Drugs 3:1255-1276 (1994).

    Google Scholar 

  9. E. Van Beek, M. Hoekstra, M. Van de Ruit, C. W. G. M. Lowik, and S. E. Papapoulos. Structural requirements for bisphosphonate actions in vitro. J. Bone Miner. Res. 9:1875-1882 (1994).

    Google Scholar 

  10. J. M. Van Gelder and G. Golomb. The evaluation of bisphosphonates as potential drugs for the treatment of calcium-related disorders. In A. Ornoy (eds.), Animal models for human related calcium metabolic disorders, CRC Press, Boca Raton, 1995, pp. 181-205.

    Google Scholar 

  11. N. V. Mikhalin, I. S. Alferiev, I. L. Kotlyarevskii, and A. V. Krasnukhina. Method of preparation of higher 1-hydroxyalkylidene-1,1-diphosphonic acids or their mixtures or salts. Russian Patent SU 1,719,405. Chem. Abst. 117:234254x (1992).

    Google Scholar 

  12. I. S. Alferiev and N. V. Mikhalin. Reactions of vinylidenediphosphonic acid with nucleophiles, Commun. 5, Addition of heterocyclic amines and trimethylamine to vinylidenediphosphonic acid. Bull. Russ. Acad. Sci., Div. Chem. Sci. 44(8):1528-1530 (1995).

    Google Scholar 

  13. L. E. King and R. Vieth. Extraction and measurement of pamidronate from bone samples using automated pre-column derivatization, high-performance liquid chromatography and fluoresence detection. J. Chromatogr. 678:325-330 (1996).

    Google Scholar 

  14. H. Cohen, V. Solomon, I. S. Alferiev, E. Breuer, A. Ornoy, N. Patlas, N. Eidelman, G. Hagele, and G. Golomb. Bisphosphonates and tetracycline: Experimental models for their evaluation in calcium-related disorders. Pharm. Res. 15(4):606-613 (1998).

    Google Scholar 

  15. P. W. Swaan, G. J. Marks, F. M. Ryan, and P. L. Smith. Determination of transport rates for arginine and acetaminophen in rabbit intestinal tissues in vitro. Pharm. Res. 11:283-287 (1994).

    Google Scholar 

  16. S. P. Robins, A. Duncan, N. Wilson, and B. J. Evans. Standardization of pyridinium crosslinks, pyridinoline and deoxypyridinoline, for use as biochemical markers of collagen degradation. Clin. Chem. 42(10):1621-1626 (1996).

    Google Scholar 

  17. J. Mönkkönen, M. Taskinen, S. O. K. Auriola, and A. Urtti. Growth inhibition of macrophage-like and other cell types by liposome-encapsulated, calcium-bound, and free bisphosphonates in vitro. J. Drug Target 2:299-308 (1994).

    Google Scholar 

  18. F. E. Nargi and T. J. Yang. Optimization of L-M cell bioassay for quantitating tumor necrosis factor in serum and plasma. J. Immunol. Methods 159:81-91 (1993).

    Google Scholar 

  19. N. Pennanen, S. Lapinjoki, A. Palander, A. Urtti, and J. Monkkonen. Macrophage-like RAW 264 cell line and time-resolved fluoroimmunoassay (TRFIA) as tools in screening drug effects on cytokine secretion. Int. J. Immunopharmacol. 17:475-480 (1995).

    Google Scholar 

  20. N. Pennanen, S. Lapinjoki, A. Urtti, and J. Monkkonen. Effect of liposomal and free bisphosphonates on the IL-1β, IL-6 and TNFα secretion from RAW 264 cells in vitro. Pharm. Res. 12:916-922 (1995).

    Google Scholar 

  21. G. Golomb, A. Schlossman, H. Saadeh, M. Levi, J. M. Van Gelder, and E. Breuer. Bisacylphosphonates inhibit hydroxyapatite formation and dissolution in vitro and dystrophic calcification in vivo. Pharm. Res. 9:143-148 (1992).

    Google Scholar 

  22. R. J. Brown, E. van Beek, D. J. Watts, C. W. Lowik, and S. E. Papapoulos. Differential effects of aminosubstituted analogs of hydroxy bisphosphonates on the growth of Dictyostelium discoideum. J. Bone. Miner. Res. 13:253-258 (1998).

    Google Scholar 

  23. J. M. Van Gelder, E. Breuer, A. Ornoy, A. Schlossman, N. Patlas, and G. Golomb. Anticalcification and antiresorption effects of bisacylphosphonates. Bone 16:511-520 (1995).

    Google Scholar 

  24. M. D. Francis and R. G. G. Russell. Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo. Science 165:1264-1266 (1969).

    Google Scholar 

  25. J. R. Green, K. Muller, and K. A. Jaeggi. Preclinical pharmacology of CGP 42′446, a new, potent, heterocyclic bisphosphonate compound. J. Bone Miner. Res. 9:745-751 (1994).

    Google Scholar 

  26. C. D. Egger, R. C. Mühlbauer, R. Felix, P. D. Delmas, S. Marks, and H. Fleisch. Evaluation of urinary pyridinium crosslinks excretion as a marker of bone resorption in the rat. J. Bone Min. Res. 9:1211-1219 (1994).

    Google Scholar 

  27. D. H. Schweitzer, M. Oostendorp-van de Ruit, G. van der Pluijm, C. W. G. M. Lowik, and S. E. Papapoulos. Interleukin-6 and the acute phase response during treatment of patients with Paget's disease with the nitrogen-containing bisphosphonate dimethylam-inohydroxypropylidene bisphosphonate. J. Bone. Miner. Res. 10:956-962 (1995).

    Google Scholar 

  28. P. L. Nicklin, W. J. Irwin, I. F. Hassan, and M. Mackay. Development of a minimum calcium Caco-2 monolayer model: calcium and magnesium ions retard the transport of pamidronate. Int. J. Pharm. 123:187-197 (1995).

    Google Scholar 

  29. S. C. Sutton, K. Engle, and J. A. Fix. Intranasal delivery of the bisphosphonate alendronate in the rat and dog. Pharm. Res. 10:924-926 (1993).

    Google Scholar 

  30. X. Boulenc, E. Marti, H. Joyeux, Y. Roques, and G. Fabre. Importance of the paracellular pathway for the transport of a new bisphosphonate using the human Caco-2 monolayers model. Biochem. Pharmacol. 46:1591-1600 (1993).

    Google Scholar 

  31. E. J. van Hoogdalem, A. T. Wackwitz, A. G. de Boer, and D. D. Breimer. 3-Amino-1-hydroxypropylidene-1, 1-diphosphonate (APD): a novel enhancer of rectal cefoxitin absorption in rats. Pharm. Pharmacol. 41:339-341 (1989).

    Google Scholar 

  32. E. G. Lufkin, R. Argueta, M. D. Whitaker, A. L. Cameron, V. H. Wong, K. S. Egan, W. M. O'Fallon, and B. L. Riggs. Pamidronate: an unrecognized problem in gastrointestinal tolerability. Osteoporosis Int. 4:320-322 (1994).

    Google Scholar 

  33. F. Lanza, M. F. Rack, T. J. Simon, A. Lombardi, R. Reyes, and S. Suryawanshi. Effects of alendronate on gastric and duodenal mucosa. Am. J. Gastroenterol. 93:753-757 (1998).

    Google Scholar 

  34. J. Mönkkönen, H. M. Koponen, and P. Yalitalo. Comparison of the distribution of three bisphosphonates in mice. Pharmacol. Toxico. 65:294-298 (1989).

    Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutics, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel

    Hagit Cohen, Taly Pinto, Aviva Ezra, David Stepensky, Hilah Sagi, Amnon Hoffman & Gershon Golomb

  2. Department of Pharmaceutical Chemistry, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel

    Ivan S. Alferiev, Vered Solomon & Eli Breuer

  3. Department of Pharmaceutics, Kuopio University, Kuopio, Finland

    Jukka Mönkkönen

  4. Department of Pharmaceutics, University of Heidelberg, Heidelberg, Germany

    Markus J. Seibel

  5. Department of Anatomy and Cell Biology, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel

    Asher Ornoy & Natan Patlas

  6. Department of Pharmaceutics, Heinrich-Heine University, Düsseldorf, Germany

    Gerhard Hägele

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  1. Hagit Cohen
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Correspondence to Gershon Golomb.

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Cohen, H., Alferiev, I.S., Mönkkönen, J. et al. Synthesis and Preclinical Pharmacology of 2-(2-Aminopyrimidinio) Ethylidene-1,1-Bisphosphonic Acid Betaine (ISA-13-1)-A Novel Bisphosphonate. Pharm Res 16, 1399–1406 (1999). https://doi.org/10.1023/A:1018951025493

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