Bisphosphonates prodrugs

R. Niemi, J. Vepsalainen, H. Taipale, T. Jarvinen, Bisphosphonate Prodrugs Synthesis and in vitro Evaluation of Novel Acyloxyalkyl Esters of Clodronic Acid , J. Med. Chem. 1999,42, 5053-5058. 

Turhanen, P.A., Ahlgren, M.J., Jarvinen, T., and Vepsalainen, J.J., Bisphosphonate prodrugs. Synthesis and identification of (1-hydroxyethylidene)-1,1-bisphosphonic acid tetraesters by mass spectrometry, NMR spectroscopy and X-ray crystallography. Phosphorus, Sulfur Silicon Relat. Elem., 170, 115, 2001. Pudovik, A.N., Batyeva, E.S., and Zamaletdinova, G.U., Reaction of a trimethylsilyl phosphite with O,O-diethyl acetyIphosphonate, Zh. Obshch. Khim., 43, 680, 1973 J. Gen. Chem. USSR (Engl. Transl.), 43, 676, 1973. 

Niemi R, Vepsalainen J, Taipale H, Jarvinen T (1999) Bisphosphonate prodrugs synthesis and in vitro evaluation of novel acyloxyalkyl esters of clodronic acid. J Med Chem 42 5053-5058... 

Monteil M, Migianu-Giiffoni E, Sainte-Catherine O, Di Benedetto M, Lecouvey M (2014) Bisphosphonate prodrugs synthesis and biological evaluation in HuH7 hepatocarcinoma cells. Eur J Med Chem 77 56-64... 

Synthesis and affinity of bisphosphonate prodrugs to target the intestinal bile acid transporter... 

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

The oral absorption of an entirely different class of drugs, namely bisphosphonates, has also been improved by a peptide prodrug strategy [36]. The drugs pamidronate (6.13, n=2) and alendronate (6.13, n=3) were deriv-atized with the Pro-Phe-dipeptidyl unit to yield the prodrugs Pro-Phe-pamidronate (6.14, n=2) and Pro-Phe-alendronate (6.14, n=3), the ob-... 

A. Ezra, A. Hoffman, E. Breuer, I. S. Alferiev, J. Monkkonen, N. El Hanany-Rozen, G. Weiss, D. Stepensky, I. Gati, H. Cohen, S. Tormalehto, G. L. Amidon, G. Golomb, A Peptide Prodrug Approach for Improving Bisphosphonate Oral Absorption , J. Med. Chem. 2000, 43, 3641-3652. 

Bisphosphonates pamidronate and alendronate (the most active bisphos-phonates approved for clinical use) were converted into the peptidyl prodrugs prolyl-phenylalanylpamidronate [Pro-Phe-pamidonate (420)] and prolyl-phenylalanyl-alendronate [Pro-Phe-alendronate (421)]. It was shown that the bioavailability of bisphosphonates can be enhanced by using the peptide prodrug approach. The increased oral absorption of the prodrugs was reduced by an active carrier-mediated transport. ... 

Ezra, A. Hoffman, A. Breuer, E. Alferiev, I.S. Monkko-nen, J. ElHanany-Rozen, N. Weiss, G. Stepensky, D. Gati, I. Cohen, H. Tormalehto, S. Amidon, G.L. Golomb, G. A peptide prodrug approach for improving bisphosphonate oral absorption. J. Med. Chem. 2000, 43, 3641-3652. 

Keywords Bisphosphonate Isoprenoid Nucleotide Phosphate Phosphonate Prodrugs... 

Some groups have evaluated prodrugs for their ability to prevent precipitation of phosphorus compounds. It has Imig been recognized that geminal bisphosphonates... 

Fig. 20 Examples of first generation bisphosphonates and a prodrug form...

Far et al. have prepared a set of 13 bisphosphonated antibacterial prodrugs of the general formula (247) for prevention of osteomyelitis infection located in bone, based on eight different linkers tethered to the free amino functionality on fluoroquinolone antibiotics. Syntheses employed tetra-ethylbisphosphonate and tetraethyl 1,1-ethenylbisphosphonate as the Michael acceptor of amine group. 

Meyers and co-workers have designed and synthesised bisphos-phonamidate prodrugs (454) that underwent intracellular activation to release the corresponding bisphosphonate and required only two enzymatic activation events to unmask multiple negative charges. ... 

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