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

• Published in: Pharmaceutical research 1999-09, Vol.16 (9), p.1399-1406
• Main Authors: COHEN, H, ALFERIEV, I. S, PATLAS, N, HÄGELE, G, HOFFMAN, A, BREUER, E, GOLOMB, G, MÖNKKÖNEN, J, SEIBEL, M. J, PINTO, T, EZRA, A, SOLOMON, V, STEPENSKY, D, SAGI, H, ORNOY, A
• Format: Article
• Language: English
• Subjects: Administration, Oral; Alendronate - chemistry; Alendronate - pharmacokinetics; Animals; Antineoplastic Agents - pharmacokinetics; Betaine - analogs & derivatives; Betaine - chemical synthesis; Betaine - pharmacokinetics; Biological and medical sciences; Bone Diseases - drug therapy; Bone Diseases - metabolism; Bone Neoplasms - drug therapy; Calcium - urine; Capsules; Carcinoma 256, Walker - drug therapy; Cell Line; Diphosphonates - chemical synthesis; Diphosphonates - pharmacokinetics; Diuretics, Osmotic - pharmacokinetics; Durapatite - chemistry; General pharmacology; Injections, Intravenous; Intestinal Absorption - drug effects; Macrophages - cytology; Macrophages - drug effects; Male; Mannitol - pharmacokinetics; Medical sciences; Osteogenesis - drug effects; Pamidronate; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Rats; Rats, Inbred Strains; Tight Junctions - drug effects; Tight Junctions - metabolism; Tissue Distribution
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1018951025493

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. 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. The solubility of the Ca salt of ISA-13-1 was higher, and the log beta(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-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. 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.