5058 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24
Niemi et al.
(17) Iyer, R. P.; Phillips, L. R.; Biddle, J . A.; Thakker, D. R.; Egan,
W.; Aoki, S.; Mitsuya, H. Synthesis of Acyloxyalkyl Acylphos-
phonates as Potential Prodrugs of the Antiviral, Trisodium
Phosphonoformate (Foscarnet Sodium). Tetrahedron Lett. 1989,
30, 7141-7144.
(18) Atack, J . R.; Prior, A. M.; Fletcher, S. R.; Quirk, K.; McKernan,
R.; Ragan, C. I. Effects of L-690,488, a Prodrug of the Bispho-
sphonate Inositol Monophosphatase Inhibitor L-690,330, on
Phosphatidylinositol Cycle Markers. J . Pharmacol. Exp. Ther.
1994, 270, 70-76.
(19) Farquhar, D.; Khan, S.; Srivastva, D. N.; Saunders: P. P.
Synthesis and Antitumor Evaluation of Bis[(pivaloyloxy)methyl]
2′-Deoxy-5-Fluorouridine 5′-Monophosphate (FdUMP): A Strat-
egy to Introduce Nucleotides into Cells. J . Med. Chem. 1994,
37, 3902-3909.
monitored at 230 nm (k′ value of 3 was determined by using
the evaporative light-scattering detector). The calibration
curve was performed with nine standard components, which
were nonionizable and had log Papp values ranging from 1.53
to 6.25. The standard compounds and their log Papp values were
as follows: anisole 2.11,32 anthracene 4.54,33 budesonide 3.55,34
hydrocortisone 1.53,35 levonorgestrel 3.70,36 naphthalene 3.30,32
nitrobenzene 1.85,32 perylene 6.25,33 and progesterone 3.87.35
The log Papp values of the standard compounds were plotted
against the measured log k′ values, and a linear relationship
(r2 ) 0.988) was found between these two parameters. The
log Papp values of the lipophilic clodronate derivatives were
determined from this linear relationship.
(20) Annaert, P.; Kinget, R.; Naesens, L.; de Clercq, E.; Augustijns,
P. Transport, Uptake, and Metabolism of the Bis(pivaloyloxym-
ethyl)-ester Prodrug of 9-(2-Phosphonylmethoxyethyl)Adenine
in an In Vitro Cell Culture System of the Intestinal Mucosa
(Caco-2). Pharm. Res. 1997, 14, 492-496.
(21) Vepsa¨la¨inen, J . Bisphosphonate Prodrugs: A New Synthesis
Strategy to Tetraacyloxymethyl Esters of Methylenebisphos-
phonates. Tetrahedron Lett. (accepted).
(22) Vepsa¨la¨inen, J . J .; Kivikoski, J .; Ahlgren, M.; Nupponen, H. E.;
Pohjola, E. K. An Improved Synthetic Method and the First
Crystal Structures for (Dihalomethylene)Bisphosphonate Partial
Esters. Tetrahedron 1995, 51, 6805-6818.
Ack n ow led gm en t. This work was financially sup-
ported by the Academy of Finland, the Technology
Development Centre (Finland), the University Phar-
macy (Finland), the Emil Aaltonen Foundation (Fin-
land) and the Kuopio University Foundation. We thank
Mrs. Maritta Salminkoski and Mrs. Helly Rissanen for
skillful technical assistance. We also thank Mrs. Sirpa
Pera¨niemi for carrying out combustion elemental analy-
ses at the University of J oensuu (Finland).
(23) Choudary, B. M.; Reddy, P. N. Vanadium-catalyzed Oxidative
Ring Cleavage of Cyclic Acetals. A Facile Synthesis of Glycol
Monoesters. Synlett 1995, 959-960.
(24) Daignault, R. A.; Eliel, E. L. 2-Cyclohexyloxyethanol. Org.
Syntheses 1973, Coll. Vol. 5, 303-306.
Refer en ces
(1) Fleisch, H. Bisphosphonates in Bone Disease: From the Labora-
tory to the Patient; The Parthenon Publishing Group Inc.: New
York, 1995.
(25) Althoff, W.; Fild, M.; Schmutzler, R. Synthesis and NMR Studies
of Alkylene/Alkylidene Bis(phosphonic dihalides) and -Bis-
(fluorophosphoranes). Chem. Ber. 1981, 114, 1082-1090.
(26) Friis, G. J .; Bundgaard, H. Design and Application of Prodrugs.
In A Textbook of Drug Design and Development, 2nd ed.;
Krogsgaard-Larsen, P., Liljefors, T., Madsen, U., Eds.; Harwood
Academic Publishers GmbH: Amsterdam, 1996; pp 351-385.
(27) Krisch, K. Carboxylic Ester Hydrolases. In The Enzymes; Boyer,
P. D., Ed.; Academic Press: New York, 1971; Vol. 5, p 57.
(28) Nielsen, N. M.; Bundgaard, H. Prodrugs as Drug Delivery
Systems. 68. Chemical and Plasma-Catalyzed Hydrolysis of
Various Esters of Benzoic Acid: A Reference System for Design-
ing Prodrug Esters of Carboxylic Acids. Int. J . Pharm. 1987, 39,
75-85.
(29) Vepsa¨la¨inen, J .; Nupponen, H.; Pohjola, E.; Ahlgren, M.; Vain-
iotalo, P. Bisphosphonic Compounds. Part 3. Preparation and
Identification of Tetraalkyl Methylene- and (R-Halomethylene)-
Bisphosphonates by Mass Spectrometry, NMR Spectroscopy and
X-ray Crystallography. J . Chem. Soc., Perkin Trans. 2 1992,
835-842.
(2) Lin, J . H. Bisphosphonates: A Review of Their Pharmacokinetic
Properties. Bone 1996, 18, 75-85.
(3) Rodan, G. A.; Fleisch, H. A. Bisphosphonates: Mechanisms of
Action. J . Clin. Invest. 1996, 97, 2692-2696.
(4) Yakatan, G. J .; Poynor, W. J .; Talbert, R. L.; Floyd, B. F.; Slough,
C. L.; Ampulski, R. S.; Benedict, J . J . Clodronate Kinetics and
Bioavailability. Clin. Pharm. Ther. 1982, 31, 402-410.
(5) Pentika¨inen, P. J .; Elomaa, I.; Nurmi, A.-K.; Ka¨rkka¨inen, S.
Pharmacokinetics of Clodronate in Patients with Metastatic
Breast Cancer. Int. J . Clin. Pharm. Ther. Toxicol. 1989, 27, 222-
228.
(6) Stella, V. J .; Charman, W. N. A.; Naringrekar, V. H. Prodrugs.
Do They Have Advantages in Clinical Practice? Drugs 1985, 29,
455-473.
(7) Waller, D. G.; George, C. F. Prodrugs. Br. J . Clin. Pharmacol.
1989, 28, 497-507.
(8) Bjo¨rkroth, J .-P.; Pakkanen, T. A.; Lindroos, J .; Pohjola, E.;
Hanhija¨rvi, H.; Lauren, L.; Hannuniemi, R.; J uhakoski, A.;
Kippo, K.; Kleimola, T. Comparative Molecular Field Analysis
of Some Clodronic Acid Esters. J . Med. Chem. 1991, 34, 2338-
2343.
(30) J a¨rvinen, T.; Suhonen, P.; Urtti, A.; Peura, P. O,O′-(1,4-Xylylene)
Bispilocarpic Acid Esters as New Potential Double Prodrugs of
Pilocarpine for Improved Ocular Delivery. II. Physicochemical
Properties, Stability, Solubility and Enzymatic Hydrolysis. Int.
J . Pharm. 1991, 75, 259-269.
(31) Lambert, W. J . Modeling Oil-Water Partitioning and Membrane
Permeation Using Reversed-Phase Chromatography. J . Chro-
matogr. A 1993, 656, 469-484.
(32) Minick, D. J .; Frenz, J . H.; Patrick, M. A.; Brent, D. A. A
Comprehensive Method for Determining Hydrophobicity Con-
stants by Reversed-Phase High-Performance Liquid Chroma-
tography. J . Med. Chem. 1988, 31, 1923-1933.
(33) Hsieh, M.-M.; Dorsey, J . G. Bioavailability Estimation by
Reversed-Phase Liquid Chromatography: High Bonding Density
C-18 Phases for Modeling Biopartitioning Processes. Anal. Chem.
1995, 67, 48-57.
(34) Nolen, H. W.; Friend, D. R. Menthol-â-D-Glucuronide: A Poten-
tial Prodrug for Treatment of the Irritable Bowel Syndrome.
Pharm. Res. 1994, 11, 1707-1711.
(35) Singh, P.; Roberts, M. S. Local Deep Tissue Penetration of
Compounds after Transdermal Application: Structure-Tissue
Penetration Relationships. J . Pharmacol. Exp. Ther. 1996, 279,
908-917.
(36) Friend, D.; Catz, P.; Heller, J .; Reid, J .; Baker, R. Transdermal
Delivery of Levonorgestrel II: Effect of Prodrug Structure on
Skin Permeability In Vitro. J . Controlled Release 1988, 7,
251-261.
(9) Ahlmark, M. J .; Vepsa¨la¨inen, J . J . Strategies for the Selective
Synthesis of Monosubstituted (Dichloromethylene)Bisphospho-
nate Esters. Tetrahedron 1997, 53, 16153-16160.
(10) Niemi, R.; Taipale, H.; Ahlmark, M.; Vepsa¨la¨inen, J .; J a¨rvinen,
T. Simultaneous Determination of Clodronate and Its Partial
Ester Derivatives by Ion-Pair Reversed-Phase High-Performance
Liquid Chromatography Coupled with Evaporative Light Scat-
tering Detection. J . Chromatogr. B 1997, 701, 97-102.
(11) Niemi, R.; Pennanen, H.; Vepsa¨la¨inen, J .; Taipale, H.; J a¨rvinen,
T. Bisphosphonate Prodrugs: Synthesis and In Vitro Evaluation
of Novel Partial Amides of Clodronic Acid. Int. J . Pharm. 1998,
174, 111-115.
(12) Ahlmark, M.; Vepsa¨la¨inen, J .; Taipale, H.; Niemi, R.; J a¨rvinen,
T. Bisphosphonate Prodrugs: Synthesis and In Vitro Evaluation
of Novel Clodronic Acid Dianhydrides as Bioreversible Prodrugs
of Clodronate. J . Med. Chem. 1999, 42, 1473-1476.
(13) Krise, J . P.; Stella, V. J . Prodrugs of phosphates, phosphonates,
and phosphinates. Adv. Drug Deliv. Rev. 1996, 19, 287-310.
(14) Starrett, J . E.; Tortolani, D. R.; Russell, J .; Hitchcock, M. J . M.;
Whiterock, V.; Martin, J . C.; Mansuri, M. M. Synthesis, Oral
Bioavailability Determination, and In Vitro Evaluation of Pro-
drugs of the Antiviral Agent 9-(2-(Phosphonomethoxy)ethyl)-
Adenine (PMEA). J . Med. Chem. 1994, 37, 1857-1864.
(15) Serafinowska, H. T.; Ashton, R. J .; Bailey, S.; Harnden, M. R.;
J ackson, S. M.; Sutton, D. Synthesis and In Vivo Evaluation of
Prodrugs of 9-(2-(Phosphonomethoxy)ethoxy)Adenine. J . Med.
Chem. 1995, 38, 1372-1379.
(16) Shaw, J .-P.; Sueoka, C. M.; Oliyai, R.; Lee, W. A.; Arimilli, M.
N.; Kim, C. U.; Cundy, K. C. Metabolism and Pharmacokinetics
of Novel Oral Prodrugs of 9-[(R)-2-(Phosphonomethoxy)-propyl]-
Adenine (PMPA) in Dogs. Pharm. Res. 1997, 14, 1824-1829.
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