Synthesis of mevalonate-and fluorinated mevalonate prodrugs and their in vitro human plasma stability

Soosung Kang, Mizuki Watanabe, J. C. Jacobs, Masaya Yamaguchi, Samira Dahesh, Victor Nizet, Thomas S. Leyh, Richard B. Silverman

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro-and 6,6,6-trifluoro-5-diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro-and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates.

Original languageEnglish (US)
Pages (from-to)448-461
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume90
DOIs
StatePublished - Jan 27 2015

Fingerprint

Mevalonic Acid
Plasma stability
Prodrugs
pyrophosphomevalonate decarboxylase
Amidohydrolases
Plasma (human)
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Acetals
In Vitro Techniques
Carbonates
Biosynthesis
Cell growth
Esterases
Amides
Pharmaceutical Preparations
Osteoporosis
Tumors
Permeability
Esters
Parasites

Keywords

  • 6 6 6-Trifluoromevalonate
  • 6-Fluoromevalonate
  • Mevalonate
  • Plasma stability
  • Prodrugs

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Kang, S., Watanabe, M., Jacobs, J. C., Yamaguchi, M., Dahesh, S., Nizet, V., ... Silverman, R. B. (2015). Synthesis of mevalonate-and fluorinated mevalonate prodrugs and their in vitro human plasma stability. European Journal of Medicinal Chemistry, 90, 448-461. https://doi.org/10.1016/j.ejmech.2014.11.040

Synthesis of mevalonate-and fluorinated mevalonate prodrugs and their in vitro human plasma stability. / Kang, Soosung; Watanabe, Mizuki; Jacobs, J. C.; Yamaguchi, Masaya; Dahesh, Samira; Nizet, Victor; Leyh, Thomas S.; Silverman, Richard B.

In: European Journal of Medicinal Chemistry, Vol. 90, 27.01.2015, p. 448-461.

Research output: Contribution to journalArticle

Kang, Soosung ; Watanabe, Mizuki ; Jacobs, J. C. ; Yamaguchi, Masaya ; Dahesh, Samira ; Nizet, Victor ; Leyh, Thomas S. ; Silverman, Richard B. / Synthesis of mevalonate-and fluorinated mevalonate prodrugs and their in vitro human plasma stability. In: European Journal of Medicinal Chemistry. 2015 ; Vol. 90. pp. 448-461.
@article{181adde115b24c9cada30a1245136833,
title = "Synthesis of mevalonate-and fluorinated mevalonate prodrugs and their in vitro human plasma stability",
abstract = "The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro-and 6,6,6-trifluoro-5-diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro-and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates.",
keywords = "6 6 6-Trifluoromevalonate, 6-Fluoromevalonate, Mevalonate, Plasma stability, Prodrugs",
author = "Soosung Kang and Mizuki Watanabe and Jacobs, {J. C.} and Masaya Yamaguchi and Samira Dahesh and Victor Nizet and Leyh, {Thomas S.} and Silverman, {Richard B.}",
year = "2015",
month = "1",
day = "27",
doi = "10.1016/j.ejmech.2014.11.040",
language = "English (US)",
volume = "90",
pages = "448--461",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - Synthesis of mevalonate-and fluorinated mevalonate prodrugs and their in vitro human plasma stability

AU - Kang, Soosung

AU - Watanabe, Mizuki

AU - Jacobs, J. C.

AU - Yamaguchi, Masaya

AU - Dahesh, Samira

AU - Nizet, Victor

AU - Leyh, Thomas S.

AU - Silverman, Richard B.

PY - 2015/1/27

Y1 - 2015/1/27

N2 - The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro-and 6,6,6-trifluoro-5-diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro-and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates.

AB - The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro-and 6,6,6-trifluoro-5-diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro-and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates.

KW - 6 6 6-Trifluoromevalonate

KW - 6-Fluoromevalonate

KW - Mevalonate

KW - Plasma stability

KW - Prodrugs

UR - http://www.scopus.com/inward/record.url?scp=84949116538&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949116538&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2014.11.040

DO - 10.1016/j.ejmech.2014.11.040

M3 - Article

VL - 90

SP - 448

EP - 461

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -