Adenosine kinase inhibitor

Fig. 1.13 Adenosine kinase inhibitor designed using fragment optimization approach.

As mentioned above, inhibition of adenosine kinase increases extracellular adenosine concentrations. Interest in enhancement of the neuroprotective, antinociceptive, and anti-inflammatory actions of adenosine has encouraged development of systemically applicable adenosine kinase inhibitor drugs. For example, it was found recently that the specific adenosine kinase inhibitor ABT-702, when given intraperitoneally, increases sleep and slow wave EEG activity of rats (Radek et al, 2004), a finding that encourages further research into the hypnogenic effect of this type of drug. 

Sinciair, C. J., et al. Nucleoside transporter subtype expression effects on potency of adenosine kinase inhibitors. Br. J. Pharmacol. 2001, 134, 1037-1044. 

Severe side-effects (hemorrhages in rats and dogs brain) have been reported after systemic application of several selected adenosine kinase inhibitors (Erion, 2000). Nevertheless, ABT-702 in particular is still reported to be in preclinical development. 

Poon, A., Sawynok, J. Antinociceptive and anti-inflammatory properties of an adenosine kinase inhibitor and an adenosine deaminase inhibitor, J. Eur. J. Pharmacol. 1999, 384, 123-138. 

Of all the nucleoside kinases, the development of adenosine kinase inhibitors has received the most attention. This can be ascribed to the unique role that adenosine plays as a secondary messenger, modulating neuronal activity... 

Figure 6.7 Nucleoside derivatives developed as adenosine kinase inhibitors by Gensia Sicor / Metabasis.

A pharmacophore model for new inhibitors was designed by Lee et al., although no inhibitory activity for the proposed inhibitors was determined experimentally.69 Long et al have designed adenosine kinase inhibitors to target Mycobacterium tuberculosis.70,71 Finally, a patent application from McMaster University disclosed phosphonates as millimolar adenosine kinase inhibitors.72... 

Adenosine kinase inhibitors take a special place in this group, due to the additional roles adenosine plays in biological processes as a second messenger. It remains to be seen whether the central nervous system side effects observed in clinical trials of GP3269 were target-mediated or compound specific. 

In the previous sections, we have discussed examples of inhibitors of nonprotein kinases for the development of novel therapeutics. Due to their important role in sugar metabolism, sugar kinase inhibitors have potential utility for the treatment of cancer, metabolic disorders diabetes and cardiovascular disease. Nucleoside kinase inhibitors are established oncology targets that operate by inhibition of the salvage pathway. Adenosine kinase inhibitors and lipid kinase inhibitors are highly significant in the development of cancer therapeutics. 

Bayburt et al., Design of adenosine kinase inhibitors from the NMR-based screening of fragments, J. Med. Chem. 2000, 43, 4781-4786. 

Uridine has been converted in seven steps into 5 -amino-3, 5 -dideoxyuridine (66), related to the 4, 5 -unsaturated structure found in the mureidomycin antibiotics. Some 5 -Amino-5 -deoxy-5-iodo-pyrrolopyrimidine nucleosides such as 67 (X = Cl, NH2) have been prepared by sodium salt glycosylation procedures, and shown to be powerful adenosine kinase inhibitors. ... 

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