- Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory Diseases
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Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone 34, a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.
- Bach, Jordi,Eastwood, Paul,González, Jacob,Gómez, Elena,Alonso, Juan Antonio,Fonquerna, Silvia,Lozoya, Estrella,Orellana, Adela,Maldonado, Mónica,Calaf, Elena,Albertí, Joan,Pérez, Juan,Andrés, Ana,Prats, Neus,Carre?o, Cristina,Calama, Elena,De Alba, Jorge,Calbet, Marta,Miralpeix, Montserrat,Ramis, Isabel
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supporting information
p. 9045 - 9060
(2019/11/03)
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- DDR2 INHIBITORS FOR THE TREATMENT OF OSTEOARTHRITIS
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The present invention relates to compounds of the formula (I) and in particular medicaments comprising at least one compound of the formula (I) for use in the treatment and/or prophylaxis of physiological and/or pathophysiological states in the triggering
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Page/Page column 139; 140
(2014/03/25)
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- Pyridin-2(1H)-one derivatives useful as medicaments for the treatment of myeloproliferative disorders, transplant rejection, immune-mediated and inflammatory diseases
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New pyridin-2(1h)-one derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
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Page/Page column 23
(2012/12/13)
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- PYRIDIN-2 (1H) -ONE DERIVATIVES USEFUL AS MEDICAMENTS FOR THE TREATMENT OF MYELOPROLIFERATIVE DISORDERS, TRANSPLANT REJECTION, IMMUNE-MEDIATED AND INFLAMMATORY DISEASES
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Compoundshaving the chemical structure of formula (I) are disclosed; as well as process for theirpreparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
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Page/Page column 68
(2012/12/13)
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- Metallation in connection with cross-coupling reactions. Coupling of hindered aryls for the synthesis of 4-phenylpyridines as part of Streptonigrin and Lavendamycin analogues
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The synthesis of the C-D ring system of Streptonigrin and Lavendamycln alkaloid analogues by cross-coupling under Suzuki's conditions has been studied. Steric hindrance is the main problem. It has been solved either by using strong bases or working in a sealed tube under pressure.
- Godard,Rocca,Pomel,Thomas-Dit-Dumont,Rovera,Thaburet,Marsais,Queguiner
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