A new class of phosphate and phosphonate prodrugs, called HepDirect prodrugs, has been developed to deliver drugs to the liver while simultaneously diminishing drug exposure to extra-hepatic tissues. The technology combines liver-selective cleavage and kinase by pass with high plasma and tissue stability to achieve increased drug levels in the liver. Lamivudine (LMV), a nucleoside analogue, is a currently approved treatment for hepatitis B infection, but shows modest efficacy and significant drug resistance due to inefficient phosphorylation. LMV is inadequately phosphorylated to the corresponding nucleoside triphosphate in rat and human hepatocytes. A HepDirect prodrug of LMV monophosphate generated 34-fold higher levels of the triphosphate in rat hepatocytes and 320-fold higher triphosphate levels in the liver of treated rats relative to LMV.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1081/ncn-200059781 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Development and validation for bioanalysis of VK2809, its active metabolite VK2809A and glutathione-conjugated metabolite MB06588 in rat liver using LC-MS/MS.
J Pharm Biomed Anal
September 2023
Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address:
VK2809 is a promising drug candidate in Phase II clinical trials for the treatment of non-alcoholic steatohepatitis (NASH). It is a prodrug with a HepDirect strategy, which can achieve selective hepatic metabolic activation, generating an active metabolite VK2809A as a potent and selective agonist for thyroid hormone receptor beta (TRβ), a concomitant reactive metabolite VK2809B, and a glutathione (GSH) conjugate MB06588. Currently, there is no convenient and sensitive bioanalytical method for the simultaneous determination of the above three metabolites.
View Article and Find Full Text PDFSelective Thyroid Hormone Receptor-Beta (TRβ) Agonists: New Perspectives for the Treatment of Metabolic and Neurodegenerative Disorders.
Front Med (Lausanne)
July 2020
Department of Pathology, University of Pisa, Pisa, Italy.
Article Synopsis
- Thyroid hormones (THs) are essential for growth, development, and metabolism, with their effects primarily mediated by two receptor types: TRα and TRβ.
- TRβ notably impacts liver health, while TRα is crucial for brain development; researchers strive to create TH analogs that differentiate beneficial effects from harmful ones, especially in the heart and muscles.
- Recent developments include selective thyroid hormone mimetics like Resmetirom and VK2809, showing promise as lipid-lowering agents in clinical trials, alongside newer compounds IS25 and TG68, evaluated for their effectiveness and safety.
Drug repurposing: phosphate prodrugs of anticancer and antiviral FDA-approved nucleosides as novel antimicrobials.
J Antimicrob Chemother
October 2020
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
Objectives: Following a drug repurposing approach, we aimed to investigate and compare the antibacterial and antibiofilm activities of different classes of phosphate prodrugs (HepDirect, cycloSal, SATE and mix SATE) of antiviral and anticancer FDA-approved nucleoside drugs [zidovudine (AZT), floxouridine (FUDR) and gemcitabine (GEM)] against a variety of pathogenic Gram-positive and -negative bacteria.
Methods: Ten prodrugs were synthesized and screened for antibacterial activity against seven Gram-negative and two Gram-positive isolates fully susceptible to traditional antibiotics, alongside six Gram-negative and five Gram-positive isolates with resistance mechanisms. Their ability to prevent and eradicate biofilms of different bacterial pathogens in relation to planktonic growth inhibition was also evaluated, together with their effect on proliferation, viability and apoptosis of different eukaryotic cells.
Biologic activity of cyclic and caged phosphates: a review.
J Appl Toxicol
January 2017
Department of Cellular Biology & Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.
The recognition in the early 1960s by Morifusa Eto that tri-o-cresyl phosphate (TOCP) is hydroxylated by the cytochrome P450 system to an intermediate that spontaneously cyclizes to a neurotoxic phosphate (saligenin phosphate ester) ignited the interest in this group of compounds. Only the ortho isomer can cyclize and clinically cause Organo Phosphate Induced Delayed Neurotoxicity (OPIDN); the meta and para isomers of tri-cresyl phosphate are not neuropathic because they are unable to form stable cyclic saligenin phosphate esters. This review identifies the diverse biological effects associated with various cyclic and caged phosphates and phosphonates and their possible use.
View Article and Find Full Text PDFLong-circulating and liver-targeted nanoassemblies of cyclic phosphoryl N-dodecanoyl gemcitabine for the treatment of hepatocellular carcinoma.
Biomed Pharmacother
April 2016
Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, China; Pharmaceutical College of Henan University, Kaifeng 475004, China. Electronic address:
Hepatocellular carcinoma (HCC) is a serious cancer with high mortality worldwide. Gemcitabine (GEM) is easily degraded in the circulation and has no tumor-targeted effect. In our previous research, an amphiphilic GEM derivative, cyclic phosphoryl N-dodecanoyl gemcitabine (CPDG) was prepared based on the techniques of HepDirect prodrug and self-assembled drug delivery systems (SADDS), which self-assembled into the stable nanoassemblies in water.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!