Journal of Medicinal Chemistry
Article
interleukin; JAK, Janus kinase; LPS, lipopolysaccharide;
LRMS, low-resolution mass spectrometry; NMR, nuclear
magnetic resonance; PAMPA, parallel artificial membrane
permeability assay; PK, pharmacokinetics; PPB, plasma protein
binding; SAR, structure−activity relationship; SEM, 2-
(trimethylsilyl)ethoxymethyl; SNAr, nucleophilic aromatic
substitution; STAT, signal transducer and activator of
transcription; TBAF, tetra-n-butylammonium fluoride;
TBDPS, tert-butyldiphenylsilyl; Tyk2, tyrosine kinase 2;
UPLC, ultraperformance liquid chromatography
AUTHOR INFORMATION
Corresponding Author
ORCID
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Present Addresses
#Premiumlab S. L., Carretera Santa Creu de Calafell 49-B, Sant
Boi de Llobregat, 08830 Barcelona, Spain (J.A.A.).
∇
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Research Center, Fundacio ACE, Institut Catala de Neuro-
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ciencies Aplicades, C/ Marques de Sentmenat 57, 08029
Barcelona, Spain (A.O.).
REFERENCES
○Admetra, C/General Ramon Despuig 17, 07013 Palma de
Mallorca, Spain (J.A.).
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(1) Leonard, W. J.; O’Shea, J. J. JAKS and STATs: Biological
implications. Annu. Rev. Immunol. 1998, 16, 293−322.
(2) Imada, K.; Leonard, W. J. The JAK-STAT pathway. Mol.
Immunol. 2000, 37, 1−11.
(3) Yamaoka, K.; Saharinen, P.; Pesu, M.; Holt, V. E. T.;
Silvennoinen, O.; O’Shea, J. J. The Janus kinases (Jaks). Genome
Biol. 2004, 5, No. 253.
◆Innoqua Toxicology Consultants, C/ Sant Antoni Maria
Claret 272 2-2, 08041 Barcelona, Spain (A.A.).
¶IRB Barcelona-Institute for Research in Biomedicine, Parc
́
Cientific de Barcelona, C/Baldiri Reixac 10, 08028 Barcelona,
Spain (N.P.).
⋈Peptinnovate, Stevenage Bioscience Catalyst, Gunnels Wood
Road, Stevenage SG1 2FX, United Kingdom (J.D.A.).
(4) O’Shea, J. J.; Pesu, M.; Borie, D. C.; Changelian, P. S. A new
modality for immunosuppression: Targeting the JAK/STAT pathway.
Nat. Rev. Drug Discovery 2004, 3, 555−564.
⧓
́
Montserrat Miralpeix Pharma Consulting, Parc Cientific de
(5) Wilks, A. F. The JAK kinases: Not just another kinase drug
discovery target. Semin. Cell Dev. Biol. 2008, 19, 319−328.
(6) Ghoreschi, K.; Laurence, A.; O’Shea, J. J. Janus kinases in
immune cell signaling. Immunol. Rev. 2009, 228, 273−287.
(7) O’Shea, J. J.; Plenge, R. JAK and STAT signaling molecules in
immunoregulation and immune-mediated disease. Immunity 2012, 36,
542−550.
(8) O’Shea, J. J.; Schwartz, D. M.; Villarino, A. V.; Gadina, M.;
McInnes, I. B.; Laurence, A. The JAK-STAT pathway: Impact on
human disease and therapeutic intervention. Annu. Rev. Med. 2015,
66, 311−328.
(9) Clark, J. D.; Flanagan, M. E.; Telliez, J.-B. Discovery and
development of Janus kinase (JAK) inhibitors for inflammatory
diseases. J. Med. Chem. 2014, 57, 5023−5038.
(10) Tam, C. S.; Verstovsek, S. Investigational Janus kinase
inhibitors. Expert Opin. Invest. Drugs 2013, 22, 687−699.
(11) Taylor, V.; Siu, S.; Young, C.; Ste Marie, L.; Ren, H.; Leusink-
Muis, T.; Van Ark, I.; Fokerts, G.; Park, G.; Pine, P.; Li, H.; Masuda,
E. R256 is a potent and selective IL-13/4 receptor signaling inhibitor
that reduces inflammation in a mouse model of chronic asthma. Am. J.
Respir. Crit. Care Med. 2012, 185, No. A2843.
(12) Ashino, S.; Takeda, K.; Pine, P. R.; Gelfand, E. W. Janus kinase
(JAK) 3 inhibitor, R256, attenuates allergen-induced airway hyper-
responsiveness and airway inflammation in mice. Am. J. Respir. Crit.
Care Med. 2012, 185, No. A2766.
(13) Jones, P.; Storer, R. I.; Sabnis, Y. A.; Wakenhut, F. M.;
Whitlock, G. A.; England, K. S.; Mukaiyama, T.; Dehnhardt, C. M.;
Coe, J. W.; Kortum, S. W.; Chrencik, J. E.; Brown, D. G.; Jones, R.
M.; Murphy, J. R.; Yeoh, T.; Morgan, P.; Kilty, I. Design and synthesis
of a pan-Janus kinase inhibitor clinical candidate (PF-06263276)
suitable for inhaled and topical delivery for the treatment of
inflammatory diseases of the lungs and skin. J. Med. Chem. 2017,
60, 767−786.
Barcelona, C/ Baldiri Reixac 4-8, 08028 Barcelona, Spain
(M.M.).
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Centro de Investigacion Biomedica en Red de Diabetes y
Enfermedades Metabolicas Asociadas (CIBERDEM), Hospital
Duran i Reynals, Gran Via 199, 08908 L’Hospitalet de
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Llobregat, Barcelona, Spain (I.R.).
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Funding
The authors were all full-time employees of Almirall S. A. at
the time this work was completed and all funding for the work
was provided by Almirall S. A.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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The authors thank Andreas Griessner, Alfred Lammens,
Michael Blaesse, and Anja Jestel from Proteros Biostructures
GmbH for X-ray structure determination of human JAK3 and
JAK1 in complex with compounds 6 and 34 (PDB codes:
6HZV and 6HZU). They also acknowledge Eva Codesido,
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Raul Fernandez, Gloria Fra, Marıa Jose Roo y Pablo Veiga
from GalChimia S. A. for their contribution to the synthesis
and scale-up of several of the compounds described in this
article. They also thank Sonia Espinosa and Josep Maria
Huerta for their support on physicochemical properties
analysis and structural characterization of compounds, Mireia
́
Verdu for her contribution to the evaluation of the activity of
(14) Wiegman, C. H.; Russell, K. E.; Seiffert, J.; Rossios, C.; Adcock,
I. M.; Rothaul, A.; Main, M.; Morgan, F. The selective pan-Janus
kinase (JAK) inhibitor VR588 demonstrates potent anti-inflammatory
activity in a murine chronic house dust mite (HDM) model of
asthma. Am. J. Respir. Crit. Care Med. 2015, 191, No. A6435.
(15) Murray, P. J. The JAK-STAT signaling pathway: input and
output integration. J. Immunol. 2007, 178, 2623−2629.
(16) Yew-Booth, L.; Birrell, M. A.; Lau, M. S.; Baker, K.; Jones, V.;
Kilty, I.; Belvisi, M. G. JAK-STAT pathway activation in COPD. Eur.
Respir. J. 2015, 46, 843−845.
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34 in ion channels, and Elena Barcelo for performing HRMS
analysis of all tested compounds.
ABBREVIATIONS
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ATP, adenosine triphosphate; AUC, area under the curve;
BAL, bronchoalveolar lavage; Boc, tert-butyloxycarbonyl;
CHO, Chinese hamster ovary; COPD, chronic obstructive
pulmonary disease; GM-CSF, granulocyte-macrophage colony-
stimulating factor; HPLC, high-performance liquid chromatog-
raphy; HRMS, high-resolution mass spectrometry; IL,
(17) Vale, K. Targeting the JAK-STAT pathway in the treatment of
‘Th2-high’ severe asthma. Future Med Chem. 2016, 8, 405−419.
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