Probing the Hydrophobic Part of Analogues of the Incadronate-Evidence of Their Interaction with Immunological System of Sheep.

Background

Thirty-five analogues of a promising antiosteoporotic drug, incadronate, have been synthesized and evaluated for their antiproliferative activity against mouse macrophage-like J774E cells. These cells originated from identical precursors as osteoclasts and served to select the most active compounds. Two of them, n-heptyl- and n-octyl-aminomethylenebispohosphonic acids, were then used for the medication of sheep with induced osteoporosis. They demonstrated mild antiosteoporotic activity that was documented using bone histopathology. Additionally, a decrease in the immunological response to Corynebacterium pseudotuberculosis was observed as a major side effect accompanied by this medication.

Methods

Aminomethylenebisphosphonates may be obtained in the three-component reaction of aliphatic amine, triethyl orthoformate and diethyl phosphite with the further acid hydrolysis of crude esters. The obtained N-substituted alkiloaminomethylenebisphosphonic acids are presented alongside with their in vitro activity toward mouse macrophages J774E.

Results

The new families of aminomethylenebisphosphonic compounds synthesized by our approach may be of practical importance due to the significant cytotoxic activity in the cell cultures investigated. Two of them were chosen for further evaluation in the treatment of induced osteoporosis in sheep.

Conclusions

In vivo studies confirmed the mild therapeutic effects of compounds 4 (N-(n-heptylamino)methylenebisphosphonic acid and 5 (N-(n-octylamino)methylenebisphosphonic acid; however, they are not suitable analogues of incadronate for consideration as potential drugs.