Synthesis and preclinical pharmacology of 2-(2-aminopyrimidinio) ethylidene-1,1-bisphosphonic acid betaine (ISA-13-1)-a novel bisphosphonate

Hagit Cohen, Ivan S. Alferiev, Jukka Mönkkönen, Markus J. Seibel, Taly Pinto, Aviva Ezra, Vered Solomon, David Stepensky, Hilah Sagi, Asher Ornoy, Natan Patlas, Gerhard Hägele, Amnon Hoffman, Eli Breuer, Gershon Golomb

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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-1,1-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 β(Ca: 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-131 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.

Original languageEnglish
Pages (from-to)1399-1406
Number of pages8
JournalPharmaceutical Research
Issue number9
StatePublished - 1999
Externally publishedYes


  • Bisphosphonates (diphosphonates)
  • Bone-related disorders
  • Calcium-related disorders
  • Drug absorption tight junctions
  • Drug administration
  • Mannitol


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