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Biological characterization of a novel class of toll-like receptor 7 agonists designed to have reduced systemic activity
Article first published online: 13 APR 2012
© 2011 AstraZeneca UK Ltd. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Novel cAMP Signalling Paradigms. Guest Editor: Martina Schmidt
Volume 166, Issue 2, pages 573–586, May 2012
How to Cite
Biffen, M., Matsui, H., Edwards, S., Leishman, A., Eiho, K., Holness, E., Satterthwaite, G., Doyle, I., Wada, H., Fraser, N., Hawkins, S., Aoki, M., Tomizawa, H., Benjamin, A., Takaku, H., McInally, T. and Murray, C. (2012), Biological characterization of a novel class of toll-like receptor 7 agonists designed to have reduced systemic activity. British Journal of Pharmacology, 166: 573–586. doi: 10.1111/j.1476-5381.2011.01790.x
- Issue published online: 13 APR 2012
- Article first published online: 13 APR 2012
- Accepted manuscript online: 29 NOV 2011 07:26AM EST
- Received; 18 April 2011; Revised; 30 September 2011; Accepted; 12 October 2011
- reporter cell;
- mononuclear cells;
BACKGROUND AND PURPOSE Toll-like receptor 7 (TLR7) agonists have potential in the treatment of allergic diseases. However, the therapeutic utility of current low molecular weight TLR7 agonists is limited by their systemic activity, resulting in unwanted side effects. We have developed a series of TLR7-selective ‘antedrugs’, including SM-324405 and AZ12441970, which contain an ester group rapidly cleaved in plasma to reduce systemic exposure.
EXPERIMENTAL APPROACH Agonist activity at TLR7 of the parent ester and acid metabolite was assessed in vitro in reporter cells and primary cells from a number of species. Pharmacokinetics following a dose to the lungs was assessed in mice and efficacy evaluated in vivo with a mouse allergic airway model.
KEY RESULTS Compounds were selective agonists for TLR7 with no crossover to TLR8 and were metabolically unstable in plasma with the acid metabolite showing substantially reduced activity in a number of assays. The compounds inhibited IL-5 production and induced IFN-α, which mediated the inhibition of IL-5. When dosed into the lung the compounds were rapidly metabolized and short-term exposure of the ‘antedrug’ was sufficient to activate the IFN pathway. AZ12441970 showed efficacy in a mouse allergic airway model with minimal induction of systemic IFN-α, consistent with the low plasma levels of compound.
CONCLUSIONS AND IMPLICATIONS The biological and metabolic profiles of these TLR7-selective agonist ‘antedrug’ compounds are consistent with a new class of compound that could be administered locally for the treatment of allergic diseases, while reducing the risk of systemic side effects.
LINKED ARTICLE This article is commented on by Kaufman and Jacoby, pp. 569–572 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01758.x