Discovery of (S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αvβ6 Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis

2018 ◽  
Vol 61 (18) ◽  
pp. 8417-8443 ◽  
Author(s):  
Panayiotis A. Procopiou ◽  
Niall A. Anderson ◽  
John Barrett ◽  
Tim N. Barrett ◽  
Matthew H. J. Crawford ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Butanoic Acid ◽  
Αvβ6 Integrin ◽  
Integrin Inhibitor

Synthesis and determination of absolute configuration of a non-peptidic αvβ6 integrin antagonist for the treatment of idiopathic pulmonary fibrosis

2016 ◽  
Vol 14 (25) ◽  
pp. 5992-6009 ◽  
Author(s):  
Niall A. Anderson ◽  
Ian B. Campbell ◽  
Brendan J. Fallon ◽  
Sean M. Lynn ◽  
Simon J. F. Macdonald ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Absolute Configuration ◽  
Determination Of Absolute Configuration ◽  
Αvβ6 Integrin ◽  
Integrin Inhibitor ◽  
Adhesion Assays

Integrin inhibitor (cell adhesion assays) pIC50 αvβ6 = 8.4, αvβ3 = 6.0, αvβ5 = 5.9 and αvβ8 = 7.7.

scholarly journals Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Alison E. John ◽  
Rebecca H. Graves ◽  
K. Tao Pun ◽  
Giovanni Vitulli ◽  
Ellen J. Forty ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Small Molecule ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Lung Epithelial Cells ◽  
Tgfβ Signaling ◽  
Lung Epithelial ◽  
Translational Pharmacology ◽  
Αvβ6 Integrin

Abstract The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

Discovery of an Orally Bioavailable Pan αv Integrin Inhibitor for Idiopathic Pulmonary Fibrosis

2019 ◽  
Vol 62 (19) ◽  
pp. 8796-8808 ◽  
Author(s):  
Niall A. Anderson ◽  
Sebastien Campos ◽  
Sharon Butler ◽  
Royston C. B. Copley ◽  
Ian Duncan ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Orally Bioavailable ◽  
Integrin Inhibitor

Role of Wnt/PCP pathway on bronchial cell function in Idiopathic Pulmonary Fibrosis

Pneumologie ◽  
2011 ◽  
Vol 65 (12) ◽  
Author(s):  
S Barkha ◽  
M Gegg ◽  
H Lickert ◽  
M Königshoff
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cell Function

Regulation of Macroautophagy in Idiopathic Pulmonary Fibrosis

Pneumologie ◽  
2012 ◽  
Vol 66 (06) ◽  
Author(s):  
P Mahavadi ◽  
S Ahuja ◽  
I Henneke ◽  
W Klepetko ◽  
C Ruppert ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis

Role of Bcl-xL in hepatocyte growth factor-elicited epithelial protection in idiopathic pulmonary fibrosis

Pneumologie ◽  
2014 ◽  
Vol 68 (06) ◽  
Author(s):  
S Skwarna ◽  
I Henneke ◽  
W Seeger ◽  
T Geiser ◽  
A Günther ◽  
...  
Keyword(s):  
Growth Factor ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Hepatocyte Growth Factor ◽  
Hepatocyte Growth

Use of nintedanib for the treatment of idiopathic pulmonary fibrosis: multi-centre real life experience in Germany

Pneumologie ◽  
2016 ◽  
Vol 70 (S 01) ◽  
Author(s):  
F Bonella ◽  
M Kreuter ◽  
L Hagmeyer ◽  
C Neurohr ◽  
K Milger ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Life Experience ◽  
Real Life
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