just got interested (but know nothing), after hearing today's Rodman and Renshaw presentation....... figures there is a bunch of biofreaks already hanging out here.
A couple of recent publications..........
J Med Chem. 2005 Oct 6;48(20):6430-41.
Adenosine kinase inhibitors. 5. Synthesis, enzyme inhibition, and analgesic activity of diaryl-erythro-furanosyltubercidin analogues.
Boyer SH, Ugarkar BG, Solbach J, Kopcho J, Matelich MC, Ollis K, Gomez-Galeno JE, Mendonca R, Tsuchiya M, Nagahisa A, Nakane M, Wiesner JB, Erion MD.
Metabasis Therapeutics Inc., 9390 Towne Centre Drive, San Diego, California 92121, USA. boyer@mbasis.com
Adenosine is an endogenous neuromodulator that when produced in the central and the peripheral nervous systems has anticonvulsant, anti-inflammatory, and analgesic properties. However, efforts to use adenosine receptor agonists are plagued by dose-limiting cardiovascular side effects. As an alternative, we explored the use of adenosine kinase inhibitors (AKIs) as potential antiseizure agents and demonstrated an adenosine receptor mediated therapeutic effect in the absence of overt cardiovascular side effects. These activities were associated with elevation of extracellular adenosine concentrations due to inhibition of AK in a site and event specific manner. Several tubercidin based AKIs, including the ribo- and lyxo-furanosyltubercidin analogues as well as the newly discovered erythro-furanosyltubercidin analogues, designed to prevent 5'-O-phosphorylation and associated toxicities, were tested for their analgesic activity in the rat formalin paw model. Described herein are the synthesis, enzyme inhibition structure-activity relationships (SARs) of erythro-furanosyltubercidin analogues, and SARs of analgesic activity of various classes of AKIs. Also reported is the characterization of a lead AKI, 19d (GP3966), an orally bioavailable compound (F% = 60% in dog) which exhibits broad-spectrum analgesic activities (ED50 < or = 4 mg/kg, per os) that are reversible with an adenosine receptor antagonist (theophylline).
Nucleosides Nucleotides Nucleic Acids. 2005;24(5-7):375-81.
Liver targeting of hepatitis-B antiviral lamivudine using the HepDirect prodrug technology.
Reddy KR, Colby TJ, Fujitaki JM, van Poelje PD, Erion MD.
Department of Chemistry, Metabasis Therapeutics, Inc., 9390 Towne Centre Drive, Building 300, San Diego, CA 92121, USA.
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.
and a link to a full text description of CS-917........
pnas.org |
