- 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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- SUBSTITUTED THIAZOLO-PYRIDINE COMPOUNDS AS MALT1 INHIBITORS
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Disclosed are compounds of the general formula (I), wherein R1-R3 are as defined herein, for use as MALT1 inhibitors in the treatment of autoimmune and inflammatory diseases or disorders. Methods of synthesizing the compounds are also disclosed. Also disc
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Page/Page column 138-139
(2018/02/28)
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- PYRIDIN-2(1H)-ONE DERIVATIVES AS JAK INHIBITORS
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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 66-67
(2013/03/26)
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- Pyridin-2(1h)-one derivatives as jak inhibitors
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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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Paragraph 0140
(2013/03/26)
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- IMIDAZO [1,2-B] PYRIDAZINE AND IMIDAZO [4,5-B] PYRIDINE DERIVATIVES AS JAK INHIBITORS
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New imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine 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 59
(2012/06/15)
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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 21-22
(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 65
(2012/12/13)
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