Synthesis and Study of Alendronate Derivatives as Potential Prodrugs of Alendronate Sodium for the Treatment of Low Bone Density and Osteoporosis

Váchal, Petr; Hale, Jeffrey J.; Lü, Zhe; Streckfuss, Eric; Mills, Sander G.; MacCoss, Malcolm; Yin, Dan; Algayer, Kimberly; Manser, Kimberly; Kesisoglou, Filippos; Ghosh, Supriya; Alani, Laman L.

doi:10.1021/jm060398v

Cited by 45 publications

(39 citation statements)

References 22 publications

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“…Signals could be attributed to each of the phosphorus atoms, the bisphosphonic esters presenting signals at higher field than the bisphosphonic acids. For the unsymmetrical bisphosphonates, the signal of the methylene carbon in 13 C NMR should have theoretically appeared as a doublet of doublets. Exper-imentally only a few products had different carbon-phosphorus coupling constantϪmost of them gave a triplet signal.…”

Section: Resultsmentioning

confidence: 99%

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Syntheses of Phosphonic Esters of Alendronate, Pamidronate and Neridronate

et al. 2007

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Section: Resultsmentioning

confidence: 99%

“…Some further developments were made by increasing lipophilicity of HMBPs. [12] Recently Vachal and coworkers [13] described (in six steps) the first alendronate prodrug. Their approach consisted in forming a myristoyl amide with the terminal amine group.…”

Section: Introductionmentioning

confidence: 99%

Syntheses of Phosphonic Esters of Alendronate, Pamidronate and Neridronate

et al. 2007

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“…Risedronate is not only an inhibitor of in vitro parasite growth but it significantly reduces the parasitemia in infected mice and increases the animal survival with no toxicity [28,29]. However, a significant clinical disadvantage of bisphosphonates is their poor oral bioavailability (less than 1 %) due to the high ionization of phosphonate groups at physiological pH [30]. This disadvantage could potentially be attenuated through coordination to a metal ion.…”

Section: Introductionmentioning

confidence: 99%

Risedronate metal complexes potentially active against Chagas disease

Demoro

Caruso

Rossi

et al. 2010

Journal of Inorganic Biochemistry

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In the search for new metal-based drugs for the treatment of Chagas disease, the most widespread Latin American parasitic disease, novel complexes of the bioactive ligand risedronate (Ris, (1-hydroxy-1-phosphono-2-pyridin-3-yl-ethyl)phosphonate), [MII(Ris)2]·4H2O, where M Cu, Co, Mn and Ni, and [NiII(Ris)2(H2O)2]·H2O were synthesized and characterized by using analytical measurements, thermogravimetric analyses, cyclic voltammetry and infrared and Raman spectroscopies. Crystal structures of [CuII(Ris)2]·4H2O and [NiII(Ris)2(H2O)2]·H2O were solved by single crystal X-ray diffraction methods. The complexes, as well as the free ligand, were evaluated in vitro against epimastigotes and intracellular amastigotes of the parasite T. cruzi, causative agent of Chagas disease. Results demonstrated that the coordination of risedronate to different metal ions improved the antiproliferative effect against Trypanosoma cruzi, exhibiting growth inhibition values against the intracellular amastigotes ranging the low micromolar levels. In addition, this strong activity could be related to high inhibition of farnesyl diphosphate synthase enzyme. On the other hand, protein interaction studies showed that all the complexes strongly interact with albumin thus providing a suitable means of transporting them to tissues in vivo.

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“…Combining both steps into a single one-pot reaction sequence without solvent in the presence of weak base simplified the overall synthetic process. This modified approach has been used to prepare N-acyl alendronate derivatives via a w-azide intermediate, reduction, acylation and finally deprotection (Scheme 5.55) [233]. Due to the poor solubility of alendronate in organic solvents, its direct N-acylation is carried out in higher yields by reaction of the disodium salt with carboxylic acid anhydrides or acyl chlorides in water [234,235].…”

Section: Synthesis Of G-aminophosphonates and Higher Homologs J219mentioning

confidence: 99%

Chemistry of Aminophosphonic Acids and Phosphonopeptides

Kukhar

Romanenko

2009

Amino Acids, Peptides and Proteins in Organic Chemistry

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Aminophosphonic (and aminophosphinic) acids occupy a prominent position in the understanding of bioprocesses in living organisms and in the construction of new bioregulators -pharmaceuticals and agrochemicals. The so-called phosphorus analogs of the amino acids, aminophosphonic and aminophosphinic acids, are amino acid mimetics in which the carboxylic group is substituted by a phosphonic acid residue P(O)(OH) 2 or phosphinic acid group P(O)(OH)R. The replacement of the carboxylic group by a phosphonic or related moiety results in a number of important consequences: the central atom of a phosphonic acid function consists of an additional substituent that has a tetrahedral configuration in contrast to the planar carbonyl atom of carboxylic group. There are also significant differences in the acidity and steric bulk of these residues. The tetrahedral configuration of the pentavalent phosphorus atom mimics the transition state of the peptide bond cleavage reaction in some enzyme-substrate interactions that is used in the synthesis of new inhibitors. The hydrolytic stability of CÀP bonds is often used in order to prepare stable analogs of bioactive phosphates OÀP(O)(OH) 2 . In addition, aminophosphonic acids and their derivatives are important as metal-complexing agents, which have diagnostic and therapeutic applications, and as industrial chemicals in water treatment, metal extraction, or pollution control.Synthesis, and the chemical, physical, and biological properties of aminophosphonic acids and some directions for their practical application are presented in a number of reviews and book chapters. The most comprehensive account of the chemistry and biology of aminophosphonates and aminophosphinate which covers literature up to 2000 is presented in Kukhar and Hudson ([1] and references therein). Readers are referred to this reference for more detailed information concerning specific aspects of the chemistry and biological activity of aminophosphonic acid derivatives. The purpose of this chapter is to give an updated report on aminophosphonic acids as analogs of amino acids. Numerous heterocyclic compounds that contain both phosphonic and amino groups will not be covered in this report.

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Synthesis and Study of Alendronate Derivatives as Potential Prodrugs of Alendronate Sodium for the Treatment of Low Bone Density and Osteoporosis

Cited by 45 publications

References 22 publications

Syntheses of Phosphonic Esters of Alendronate, Pamidronate and Neridronate

Syntheses of Phosphonic Esters of Alendronate, Pamidronate and Neridronate

Risedronate metal complexes potentially active against Chagas disease

Chemistry of Aminophosphonic Acids and Phosphonopeptides

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