Orally active squalene synthase inhibitors: Bis((acyloxy)alkyl) prodrugs of the α-phosphonosulfonic acid moiety

Journal of Medicinal Chemistry

Volumn 39, Issue 3, 1996, Pages 661-664

  Dickson Jr , John K ^a   Biller, Scott A ^a   Magnin, David R ^a   Petrillo Jr , Edward W ^a   Hillyer, John W ^a   Hsieh, Dolly C ^a   Lan, Shih Jung ^a   Rinehart, J Kent ^a   Gregg, Richard E ^a   Harrity, Thomas W ^a   Jolibois, Kern G ^a   Kalinowski, Stephen S ^a   Kunselman, Lori K ^a   Mookhtiar, Kasim A ^a   Ciosek Jr , Carl P ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA PHOSPHONOSULFONIC ACID DERIVATIVE; BISPHOSPHONIC ACID DERIVATIVE; HYPOCHOLESTEROLEMIC AGENT; SQUALENE SYNTHASE; SQUALENE SYNTHASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CHOLESTEROL SYNTHESIS; DRUG BIOAVAILABILITY; DRUG EXCRETION; ENZYME INHIBITION; LIVER TOXICITY;

ADMINISTRATION, ORAL; ANIMALS; ANTILIPEMIC AGENTS; ENZYME INHIBITORS; FARNESYL-DIPHOSPHATE FARNESYLTRANSFERASE; GUINEA PIGS; PRODRUGS; RATS; SULFONIC ACIDS;

EID: 13344277992     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm950735s     Document Type: Article

References (33)

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2. Bundgaard, H. In A Textbook of Drug Design and Development; Krogsgaard-Larsen, P., Bundgaard, H., Eds.; Harwood Academic: Philadelphia, 1991; Chapter 5.
3. 14C]-1 or one of the esters in Table 1. Bile, urine, and feces were collected from each animal for 12 h. Animals were sacrificed at 12 h after dosing. Radioactivity in all samples, including the carcass, was determined by liquid scintillation counting. The absorption was estimated by the sum of radioactivity recovered in bile, urine, and carcass (minus the gastrointestinal tract).
4. Incubation of triester 5 with boiled plasma and boiled homogenates of liver and intestines from rats (4 h, 37°C) all resulted in the extensive conversion of triester 5 to the diester 4, presumably via a solvolytic mechanism.
5. In two cases, diphenyl esters of phosphonates have been used successfully as prodrugs to improve oral absorption: (a) Serafinowska, H. T.; Ashton, R. J.; Bailey, S.; Harnden, M. R.; Jackson, S. J.; Sutton, D. Synthesis and in Vivo Evaluation of Prodrugs of 9-[2-(Phosphonomethoxy)ethoxy]adenine. J. Med. Chem. 1995, 38, 1372-1379. (b) De Lombaert, S.; Erion, M. D.; Tan, J.; Blanchard, L.; El-Chehabi, L.; Ghai, R. D.; Sakane, Y.; Berry, C.; Trapani, A. J. N-Phosphonomethyl Dipeptides and Their Phosphonate Prodrugs, a New Generation of Neutral Endopeptidase (NEP, EC 3.4.24.11) Inhibitors. J. Med. Chem. 1994, 37, 498-511.
6. In two cases, diphenyl esters of phosphonates have been used successfully as prodrugs to improve oral absorption: (a) Serafinowska, H. T.; Ashton, R. J.; Bailey, S.; Harnden, M. R.; Jackson, S. J.; Sutton, D. Synthesis and in Vivo Evaluation of Prodrugs of 9-[2-(Phosphonomethoxy)ethoxy]adenine. J. Med. Chem. 1995, 38, 1372-1379. (b) De Lombaert, S.; Erion, M. D.; Tan, J.; Blanchard, L.; El-Chehabi, L.; Ghai, R. D.; Sakane, Y.; Berry, C.; Trapani, A. J. N-Phosphonomethyl Dipeptides and Their Phosphonate Prodrugs, a New Generation of Neutral Endopeptidase (NEP, EC 3.4.24.11) Inhibitors. J. Med. Chem. 1994, 37, 498-511.
7. 14C]-1 after an intravenous dose. These results suggest that the phosphonate esters were not bioconverted to the active acid in rats.
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13. Another strategy relying on remote hydroylsis is based on 4-acyloxybenzyl esters: Mitchell, A. G.; Thomson, W., Nicholls, D.; Irwin, W. J.; Freeman, S. Bioreversible Protection for the Phospho Group: Bioactivation of the Di(4-acyloxybenzyl) and Mono(4-acyloxybenzyl) Phosphoesters of Methylphosphonate and Phosphonoacetate. J. Chem. Soc., Perkin Trans. 1 1992, 2345-2353
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15. (a) Farquhar, D.; Khan, S.; Wilkerson, M. C.; Andersson, B. S. Biologically-Cleavable Phosphate Protective Groups: 4-Acyloxy-1,3,2-Dioxaphosphorinanes as Neutral Latent Precursors of Dianionic Phosphates. Tetrahedron Lett. 1995, 36, 655-658.
16. (b) Starrett, J. E., Jr.; Tortolani, D. R.; Russell, J.; Hitchcock, M. J. M.; Whiterock, V.; Martin, J. C.; Mansuri, M. M. Synthesis, Oral Bioavailability Determination, and in Vivo Evaluation of Prodrugs of the Antiviral Agent 9-[2-(Phosphonomethoxy)ethyl]-adenine (PMEA). J. Med. Chem. 1994, 37, 1857-1864.
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21. The procedure utilized for the rat model of cholesterol biosynthesis is detailed in ref 12.
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23. 14 Briefly, 30 μL of a 0.5% (w/v) solution of methylbenzothiazolinehydrazone was added to the quenched reaction mixture, the mixture vortexed and incubated at room temperature for 30 min. To this was added 150 μL of 0.25% (w/v) ferric chloride, and the mixture was vortexed and incubated for a further 10 min. Finally, the mixture was diluted with 450 μL of water and allowed to stand at room temperature for 60 min before measuring the absorbance at 625 nm. The corresponding aldehyde was used for a standard curve for quantitation. The esterase susceptibility of 9 was 3.7 pmol of aldehyde released/min per unit esterase, where one unit of esterase is defined as the amount of enzyme which will hydrolyze 1 nmol of 4-nitrophenylacetate/min at 25°C and pH 7.0 at a substrate concentration of 0.7 mM. No attempt was made to differentiate between the rates of hydrolysis of the diester and the subsequently formed monoester. For prodrugs 6, 8, 9, and 15, > 1 equiv of aldehyde was released during the assay period (3 h), indicating that the second ester was cleaved. In addition, the complete enzymatic hydrolyses of 9 to 1 and 15 to 2 have been demonstrated in the cytosolic fractions of rat liver and intestinal homogenates. In the latter experiments, the formation of 1 and 2 was assayed by an HPLC method with UV detection.
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25. The hamster cholesterol-lowering model was executed as described in ref 12.
26. The systemic bioavailability of 2 in rats was calculated on the basis of the ratios of areas under the plasma concentration of 2 vs time curve after an intravenous dose of 2 and an oral dose of 15. The concentration of 2 was measured by an HPLC method with UV detection.
27. The systemic bioavailability of the (S)-enantiomer of 2 upon oral dosing of the tripotassium salt was <3%.
28. The hepatic bioavailability of 2 was calculated on the basis of the ratios of the amounts of 2 excreted in bile after an intravenous dose of 2 and an oral dose of 15. The concentration of 2 was measured by an HPLC-UV assay.
29. We cannot rule out the possibility that the absorption of monoester 22 is making a contribution to the bioavailability of 2 on dosing the diester 15.
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31. Iodides 25 were prepared according to ref 10e, and references cited therein.
32. A number of deprotection conditions were attempted in order to prevent formation of the monoester byproduct. These included nucleophilic displacement with iodide, thiophenoxide, or azide and elimination with DBU; however, in all cases, the undesired monoester was a major contaminant of the reaction.
33. Ulich, L. H.; Adams, R. The Reaction Between Acid Halides and Aldehydes. J. Am. Chem. Soc. 1921, 43, 660-667.