Synthesis of highly water-soluble fibrate derivatives via BGLation

Nemoto, Hisao; Kamiya, M.; Nakamoto, Aki; Matsushita, Tetsuya; Matsumura, Kosuke; Hattori, Hatsuhiko; Kawamura, Tomoyuki; Taoka, Chiaki; Abe, Shinji; Ishizawa, Keisuke; Miyamoto, Licht; Tsuchiya, Koichiro

doi:10.1016/j.bmcl.2012.08.057

Cited by 9 publications

(9 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus BGLation of fenofibrate may be beneficial to its ADME properties by ameliorating absorption and distribution. We also preliminarily confirmed that lipid-lowering effect of FF-BGL was not impaired using normal rats (Nemoto et al, 2012c). Further study on ADME profiles of FF-BGL is required to clarify comprehensive pharmacological benefit of BGLation of fenofibrate.…”

Section: Resultsmentioning

confidence: 48%

“…Recently we succeeded in synthesizing a novel molecule, BGL003-conjugated fenofibrate (FF-BGL) (Fig. 1C) (Nemoto et al, 2012c). Fenofibrate is a popular peroxisome proliferator-activated receptor (PPAR) α agonist clinically used as an anti-hyperlipidemic drug and is known for its exceptionally hydrophobic character.…”

Section: Resultsmentioning

confidence: 99%

“…BGL003 (1,3-bis[(2,2-dimethyl-1,3-dioxan-5-yl)oxy]-2-propanol) and fenofibrate-BGL003 conjugate (FF-BGL) (Fig. 1C) were synthesized as described elsewhere Nemoto et al, 2007bNemoto et al, , 2010Nemoto et al, , 2012c.…”

Section: Materials and Reagentsmentioning

confidence: 99%

See 2 more Smart Citations

Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells

et al. 2012

Self Cite

View full text Add to dashboard Cite

-An appropriate balance between lipophilicity and hydrophilicity is necessary for pharmaceuticals to achieve fine Absorption, Distribution, Metabolism and Excretion (ADME) properties including absorption and distribution, in particular. We have designed and proposed symmetrically branched oligoglycerols (BGL) as an alternative approach to improve the lipophilic-hydrophilic balance. We have previously shown that stability in circulation and water-solubility of such molecules as proteins, liposomes and hydrophobic compounds are much improved by conjugation to BGL. Albeit these successful applications of BGL, little was known whether BGL could be used in safety. Thus we conducted evaluation of the cytotoxicity of a representative BGL, symmetrically branched glycerol trimer (BGL003) in the cultured cells to clarify its biological safeness. Here we demonstrate that water-solubility of an extremely hydrophobic agent, fenofibrate was more than 2,000-fold improved just by conjugated with BGL003. BGL003 did not exhibit any significant cytotoxicity in human hepatocarcinoma HepG2 cells. Thus BGL003 should be safe and suitable strategy to endow hydrophobic molecules with much hydrophilicity.

show abstract

Section: Resultsmentioning

confidence: 48%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…1E) (Nemoto et al, 2012c;Miyamoto et al, 2012). We recently noticed that the BGL003-conjugated fenofibrate yielded an active form of fenofibrate, fenofibric acid (Fig.…”

Section: Resultsmentioning

confidence: 95%

“…We recently noticed that the BGL003-conjugated fenofibrate yielded an active form of fenofibrate, fenofibric acid (Fig. 1D) when administered in vivo, suggesting that BGL003 should be easily applicable to prodrug (Nemoto et al, 2012c). However, the safety of BGL003 will concern its success in future clinical development as BGL003 should be cleft off in vivo.…”

Section: Resultsmentioning

confidence: 99%

Acute oral toxicity evaluation of symmetrically branched glycerol trimer in ddY mice

et al. 2012

Self Cite

View full text Add to dashboard Cite

-Lipophilic-hydrophilic balance is a quite important determinant of pharmacokinetic properties of pharmaceuticals. Thus it is a key step to successfully manage lipophilic-hydrophilic balance in drug design. We have designed unique modular molecules, symmetrically branched oligoglycerols (BGL) as an alternative means to endow hydrophobic molecules with much hydrophilicity. We have succeeded in improving the water-solubility of several hydrophobic medicinal small molecules and thermal stability of artificial protein by covalent conjugation to BGL. We have also demonstrated that a representative BGL, symmetrically branched glycerol trimer (BGL003) does not exhibit significant cytotoxicity against human hepatocarcinoma HepG2 cells. However, there have been no reports suggesting whether BGL could be used in safety in vivo. Therefore, evaluation of acute oral toxicity of BGL003 in healthy mice was conducted. Here we demonstrate that an oral administration of BGL003 did not exhibit acute lethal toxicity up to 3,000 mg/kg. Body weight, food intake, blood glucose levels and weights of tissues were not affected by a short-term repetitive administration of increasing doses of BGL003. Biochemical indications related to hepatic disorders and tissue damage were unchanged, either. A single administration study revealed that 50% lethal dose of BGL003 should be more than 2,000 mg/kg. BGL003 will be safe and suitable approach to improve hydrophilicity of hydrophobic compounds.

show abstract

Storable protection-free BGL reagents possessing a bioorthogonal functional group at apex

et al. 2022

View full text Add to dashboard Cite

Synthesis of highly water-soluble fibrate derivatives via BGLation

Cited by 9 publications

References 35 publications

Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells

Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells

Acute oral toxicity evaluation of symmetrically branched glycerol trimer in ddY mice

Storable protection-free BGL reagents possessing a bioorthogonal functional group at apex

Contact Info

Product

Resources

About