共 34 条
Biological characterization of a novel class of toll-like receptor 7 agonists designed to have reduced systemic activity
被引:30
作者:

Biffen, M.
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h-index: 0
机构:
AstraZeneca R&D Charnwood, Dept Biosci, Loughborough, Leics, England AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Matsui, H.
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h-index: 0
机构:
Dainippon Sumitomo Pharma Co Ltd, Pharmacol Res Lab, Osaka, Japan AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Edwards, S.
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h-index: 0
机构:
AstraZeneca R&D Charnwood, Dept Biosci, Loughborough, Leics, England AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Leishman, A. J.
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机构:
AstraZeneca R&D Charnwood, Dept Biosci, Loughborough, Leics, England AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Eiho, K.
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h-index: 0
机构:
Dainippon Sumitomo Pharma Co Ltd, Pharmacol Res Lab, Osaka, Japan AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Holness, E.
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h-index: 0
机构:
AstraZeneca R&D Charnwood, Dept Biosci, Loughborough, Leics, England AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Satterthwaite, G.
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AstraZeneca R&D Charnwood, Dept Biosci, Loughborough, Leics, England AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Doyle, I.
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AstraZeneca R&D Charnwood, Dept Biosci, Loughborough, Leics, England AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Wada, H.
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AstraZeneca R&D Charnwood, Dept Med Chem, Loughborough, Leics, England AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Fraser, N. J.
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AstraZeneca R&D Charnwood, Dept Biosci, Loughborough, Leics, England AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Hawkins, S. L.
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AstraZeneca R&D Charnwood, Dept Biosci, Loughborough, Leics, England AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Aoki, M.
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Dainippon Sumitomo Pharma Co Ltd, Pharmacol Res Lab, Osaka, Japan AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Tomizawa, H.
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Dainippon Sumitomo Pharma Co Ltd, Pharmacol Res Lab, Osaka, Japan AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Benjamin, A. D.
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AstraZeneca R&D Charnwood, Dept Biosci, Loughborough, Leics, England AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Takaku, H.
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h-index: 0
机构:
Dainippon Sumitomo Pharma Co Ltd, Pharmacol Res Lab, Osaka, Japan AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

McInally, T.
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h-index: 0
机构:
AstraZeneca R&D Charnwood, Dept Med Chem, Loughborough, Leics, England AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England

Murray, C. M.
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h-index: 0
机构:
AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England
机构:
[1] AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England
[2] AstraZeneca R&D Charnwood, Dept Biosci, Loughborough, Leics, England
[3] AstraZeneca R&D Charnwood, Dept Med Chem, Loughborough, Leics, England
[4] Dainippon Sumitomo Pharma Co Ltd, Pharmacol Res Lab, Osaka, Japan
关键词:
allergy;
cytokines;
lung;
reporter cell;
mononuclear cells;
splenocytes;
TLR7;
CYTOKINE INDUCTION;
MODIFIED ADENINE;
IMMUNE-RESPONSE;
HUMAN TLR7;
ASTHMA;
RECOGNITION;
DERIVATIVES;
PREVALENCE;
EFFICACY;
CELLS;
D O I:
10.1111/j.1476-5381.2011.01790.x
中图分类号:
R9 [药学];
学科分类号:
1007 ;
摘要:
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-alpha, 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-alpha, 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.
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收藏
页码:573 / 586
页数:14
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Gorski, KS
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Gibson, SJ
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Kedl, RM
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3M Co, 3M Ctr, St Paul, MN 55144 USA 3M Co, 3M Ctr, St Paul, MN 55144 USA

Kieper, WC
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Qiu, XH
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Tomai, MA
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Alkan, SS
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Vasilakos, JP
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Coffman, R. L.
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Barrat, F. J.
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Hanten, John A.
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3M Pharmaceut, Dept Pharmacol, St Paul, MN 55144 USA
3M Drug Delivery Syst, St Paul, MN 55144 USA 3M Pharmaceut, Dept Pharmacol, St Paul, MN 55144 USA

Vasilakos, John P.
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Biothera, Eagan, MN 55121 USA 3M Pharmaceut, Dept Pharmacol, St Paul, MN 55144 USA

Riter, Christie L.
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3M Pharmaceut, Dept Pharmacol, St Paul, MN 55144 USA 3M Pharmaceut, Dept Pharmacol, St Paul, MN 55144 USA

Neys, Lori
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3M Pharmaceut, Dept Pharmacol, St Paul, MN 55144 USA
DiaSorin Inc, Stillwater, MN 55082 USA 3M Pharmaceut, Dept Pharmacol, St Paul, MN 55144 USA

Lipson, Kenneth E.
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3M Pharmaceut, Dept Pharmacol, St Paul, MN 55144 USA
FibroGen Inc, San Francisco, CA 94080 USA 3M Pharmaceut, Dept Pharmacol, St Paul, MN 55144 USA

Alkan, Sefik S.
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3M Pharmaceut, Dept Pharmacol, St Paul, MN 55144 USA
Alba Therapeut Corp, Baltimore, MD 21201 USA 3M Pharmaceut, Dept Pharmacol, St Paul, MN 55144 USA

Birmachu, Woubalem
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3M Pharmaceut, Dept Pharmacol, St Paul, MN 55144 USA
3M Med, St Paul, MN 55144 USA 3M Pharmaceut, Dept Pharmacol, St Paul, MN 55144 USA