Rapid cleavage leads to better liver drugs

Novel compounds help the body accept DNA-based drugs.

Researchers from a US biotechnology company called Metabasis Therapeutics have discovered a novel class of phosphate- and phosphonate-based compounds that are able to target nucleoside-based drugs at the liver. These prodrug compounds, termed HepDirect, could help to treat a range of liver diseases and Metabasis already has two drug candidates based on this technology in clinical development.

Drugs based on nucleosides, which are DNA components that lack a phosphate group, have proved useful in treating viral infections and leukaemia. Within the body, the nucleosides are converted into nucleoside triphosphates (NTPs), which can interfere with viral replication and cell proliferation. Unfortunately, being genetic material, these drugs often suffer from problems relating to toxicity and lack of efficacy, which has limited their potential for treating liver diseases. To overcome these problems, the Metabasis researchers decided to try to develop nucleoside prodrugs that would only become active within the liver.

The researchers based their compounds on two commercialised prodrugs for treating cancer, which are derived from cyclic 1,3-propanyl esters. These prodrugs are cleaved within the liver, activating the attached nucleoside. However, the process is fairly slow, giving the compounds time to distribute within the body. The researchers wanted to develop a prodrug where the cleavage process in the liver was much faster, preventing the active nucleoside from leaving the organ.

To do this, they developed a range of 1-aryl 1,3-propanediols, each containing a C4 aryl substituent in the cis-configuration. The researchers discovered that this compound would only undergo an oxidative cleavage reaction in the presence of a specific protein, known as cytochrome P450, which is predominantly expressed in the liver. Not only did this reaction happen quickly, but the activated nucleoside is also negatively charged, which means that it is unable to escape from the liver cells.

Testing the prodrug with an attached nucleoside in rats, the researchers found much higher levels of NTPs in the rats’ livers than when the nucleoside was administered on its own. Metabasis is now developing two nucleoside drug candidates using the HepDirect technology for treating hepatitis B and primary liver cancer.

Jon Evans