ADME

Characteristic physical properties and structural fragments of marketed oral drugs. Vieth, M. et al. J. Med. Chem. 26 Nov 2003 (doi: 10.1021/jm030267j).

Understanding how the physical properties of molecules influence their pharmacokinetics is important for improving the probability of selecting successful clinical candidates, and so has been the subject of considerable study. Vieth et al. have compiled both structural and route-administration information for 1,729 marketed drugs — which they have made freely available online — to provide a basis for developing a new perspective on the characteristics of orally administered drugs.

Anticancer Drugs

A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Rubin, J. B. et al. Proc. Natl Acad. Sci. USA 100, 13513–13518 (2003).

Malignant brain tumours are a major cause of cancer mortality in both adults and children. Rubin et al. show that antagonism of the chemokine receptor CXCR4 by the small molecule AMD 3100 inhibits the growth of brain tumours in vivo in mice. This finding could rapidly lead to clinical trials, as AMD 3100 is already known to be well tolerated in humans from studies of this agent as a potential anti-HIV treatment.

Liver Disease

Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. Liu, Y. et al. J. Clin. Invest. 17 Nov 2003 (doi: 10.1172/JCI200318945).

Cholestasis, an impairment or cessation in the flow of bile, causes hepatotoxicity as a result of the accumulation of bile acids and other toxins in the liver. As activation of the farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, is known to induce transcription of genes involved in promoting bile-acid clearance and to repress genes involved in bile-acid synthesis, the authors tested the synthetic FXR agonist GW4064 in rat models of cholestasis, and their results indicate that FXR agonists could be useful in the treatment of cholestatic liver disease.

Screening

Competitive binding assays made easy with a native marker and mass spectrometric quantification. Höfner, G. & Wanner, K. T. Angew. Chem. Int. Ed. 42, 5235–5237 (2003).

Competitive binding assays are a key method in drug discovery, but typically require the use of marker ligands labelled either with a radioisotope or a fluorophore, which can have several limitations. The authors describe a simple competitive binding assay based on mass spectrometry that does not require labelled ligands.