Parking a first pass at relevant abstracts and papers:
First, an overview of one of their platform technologies:
>>J Pharmacol Exp Ther. 2004 Aug 31; [Epub ahead of print]
Liver-Targeted Drug Delivery Using HepDirectTM Prodrugs.
Erion MD, Van Poelje PD, MacKenna DA, Colby TJ, Montag A, Fujitaki JM, Linemeyer DL, Bullough DA.
Inc.
Targeting drugs to specific organs, tissues or cells is an attractive strategy for enhancing drug efficacy and reducing side effects. Drug carriers such as antibodies, natural and man-made polymers and labeled liposomes are capable of targeting drugs to blood vessels of individual tissues, but often fail to deliver drugs to extravascular sites. An alternative strategy is to use low molecular weight prodrugs that distribute throughout the body but cleave intracellularly to the active drug by an organ-specific enzyme. Here we show that a series of phosphate and phosphonate prodrugs, called HepDirect(TM) prodrugs, results in liver-targeted drug delivery following a cytochrome P450-catalyzed oxidative cleavage reaction inside hepatocytes. Liver targeting was demonstrated in rodents for MB06866, a HepDirect prodrug of the nucleotide analogue adefovir (PMEA), and MB07133, a HepDirect prodrug of cytarabine (araC) 5'-monophosphate. Liver targeting led to higher levels of the biologically active form of PMEA and araC in the liver and to lower levels in the toxicologically most sensitive organs. Liver targeting also confined production of the prodrug byproduct, an aryl vinyl ketone, to hepatocytes. Glutathione within the hepatocytes rapidly reacted with the byproduct to form a glutathione conjugate. No byproduct-related toxicity was observed in hepatocytes or animals treated with HepDirect prodrugs. A 5-day safety study in mice demonstrated the toxicological benefits of liver targeting. These findings suggest that HepDirect prodrugs represent a potential strategy for targeting drugs to the liver and achieving more effective therapies against chronic liver diseases such as hepatitis B, hepatitis C and hepatocellular carcinoma.<<
Below is the last of three papers on AKIs:
>>J Med Chem. 2003 Oct 23;46(22):4750-60.
Adenosine kinase inhibitors. 3. Synthesis, SAR, and antiinflammatory activity of a series of l-lyxofuranosyl nucleosides.
Ugarkar BG, Castellino AJ, DaRe JS, Ramirez-Weinhouse M, Kopcho JJ, Rosengren S, Erion MD.
Metabasis Therapeutics, Inc., 9390 Towne Centre Drive, San Diego, California 92121, USA. ugarkar@mbasis.com
Chronic inflammatory diseases, such as arthritis and rheumatoid arthritis, remain major health problems worldwide. We previously demonstrated that adenosine kinase inhibitors (AKIs) exhibit antiinflammatory effects by inhibiting TNF-alpha production, neutrophil accumulation, and edema formation. Although adenosine receptor agonists produce similar effects, AKIs showed the antiinflammatory activity without the cardiovascular side effects that prevented the development of adenosine receptor specific agonists. However, previously described potent AKIs, such as 5-iodotubercidin, are nucleosides which have the potential to undergo in vivo 5'-O-phosphorylation and therefore produce cytotoxicity. In an effort to eliminate toxicities produced by phosphorylated nucleosides, l-lyxofuranosyl analogues of tubercidin were tested as potential AKIs since the opposite stereochemical orientation of the CH(2)OH was expected to eliminate intracellular phosphorylation. Described herein are the discovery of a new series of AKIs based on alpha-l-lyxofuranosyl nucleosides, their SAR, as well as the antiinflammatory activity of the lead compound GP790 (IC(50) = 0.47 nM, 47% inhibition of paw swelling at 10 mg/kg in rat carrageenan paw edema model). In addition, a study showing that in the skin lesion model the antiinflammatory activity is reversed by an A2 selective adenosine receptor antagonist 3,7-dimethyl-1-propargyl xanthine [correction of propylxanthine] (DMPX) is also described.<<
"Adenosine kinase inhibitors as a novel approach to anticonvulsant therapy."
jpet.aspetjournals.org
Old, but a full text freebie.
>>J Med Chem. 2001 Feb 15;44(4):613-8.
AMP deaminase inhibitors. 5. Design, synthesis, and SAR of a highly potent inhibitor series.
Kasibhatla SR, Bookser BC, Xiao W, Erion MD.
Metabasis Therapeutics Inc., 9390 Towne Centre Drive, San Diego, California 92121, USA. rao@mbasis.com
A highly potent AMP deaminase (AMPDA) inhibitor series was discovered by replacing the N3 substitutents of the two lead AMPDA inhibitor series with a conformationally restricted group. The most potent compound, 3-[2-(3-carboxy-4-bromo-5,6,7,8-tetrahydronaphthyl)ethyl]-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (24b), represents a 10- to 250-fold enhancement in AMPDA inhibitory potency without loss in the enzyme specificity. The potency of the inhibitor 24b (AMPDA K(i) = 0.002 microM) is 10(5)-fold lower than the Km for the substrate AMP. It represents the most potent nonnucleotide AMPDA inhibitor known.<<
There are 4 other earlier papers in this AMPDA series.
I'm sure there's nore stuff. I'll post it when I get a chance.
Cheers, Tuck |
