- 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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- Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment. 12. Structure-activity relationships associated with 4-fluoro-6-azaindole derivatives leading to the identification of 1-(4-benzoylpiperazin-1-yl)-2-(4- fluoro-7-[1,2,3]triazol-1-yl-1H-
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A series of highly potent HIV-1 attachment inhibitors with 4-fluoro-6-azaindole core heterocycles that target the viral envelope protein gp120 has been prepared. Substitution in the 7-position of the azaindole core with amides (12a,b), C-linked heterocycl
- Regueiro-Ren, Alicia,Xue, Qiufen M.,Swidorski, Jacob J.,Gong, Yi-Fei,Mathew, Marina,Parker, Dawn D.,Yang, Zheng,Eggers, Betsy,D'Arienzo, Celia,Sun, Yongnian,Malinowski, Jacek,Gao, Qi,Wu, Dedong,Langley, David R.,Colonno, Richard J.,Chien, Caly,Grasela, Dennis M.,Zheng, Ming,Lin, Pin-Fang,Meanwell, Nicholas A.,Kadow, John F.
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p. 1656 - 1669
(2013/04/23)
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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 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 66
(2012/12/13)
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- TRIAZOLE DERIVATIVES AS VASOPRESSIN ANTAGONISTS
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Compounds of formula (I), or pharmaceutically acceptable derivatives thereof, wherein: R1 represents a group selected from H, CF3, and C1-6 alkyl (optionally substituted by C1-6 alkyloxy or triazolyl); R2/
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Page/Page column 45
(2010/11/24)
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- Aminium salts of 1,2,3-triazoles as prodrugs of drugs including antiviral agents
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This disclosure provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the disclosure is concerned with new aminium salts of 1,2,3-triazoles which can be used as prodrugs to improve
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Page/Page column 11; 13-14
(2008/06/13)
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- Prodrugs of piperazine and substituted piperidine antiviral agents
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This invention provides for prodrug Compounds I, pharmaceutical compositions thereof, and their use in treating HIV infection. wherein: X is C or N with the proviso that when X is N, R1 does not exist; W is C or N with the proviso that when W is N, R2 does not exist; V is C; E is hydrogen or a pharmaceutically acceptable salt thereof; and Y is selected from the group consisting of Also, this invention provides for intermediate Compounds II useful in making prodrug Compounds I. wherein: L and M are independently selected from the group consisting of C1-C6 alkyl, phenyl, benzyl, trialkylsilyl, -2,2,2-trichloroethoxy and 2-trimethylsilylethoxy.
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Page/Page column 31
(2010/02/14)
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- Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives
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This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with azaindoleoxoacetyl piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.
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- Indole, azaindole and related heterocyclic sulfonylureido piperazine derivatives
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This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with sulfonylureido piperazine derivatives of Formula I. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS. 1wherein: Z is 2Q is selected from the group consisting of: 3—W— is 4—represents a carbon-carbon bond or does not exist; and A is NR13R14.
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Page/Page column 37
(2010/02/05)
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- INDOLE, AZAINDOLE AND RELATED HETEROCYCLIC UREIDO AND THIOUREIDO PIPERAZINE DERIVATIVES
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This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with ureido and thioureido piperazine derivatives of Formula (I). These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS. The compounds of Formula (I) are Formula (I) wherein:Y is O or S;Z is Formula (II); Q is selected from the group consisting of Formula (A) and Formula (B); m is 2;A is NRR; and-W- is Formula (C).
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- Indole, azaindole and related heterocyclic 4-alkenyl piperidine amides
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This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with new piperidine 4-alkenyl derivatives that possess unique antiviral activity. More particularly, the present invention relates to compounds useful for the treatment of HIV and AIDS. The compounds of the invention for the general Formula I: wherein: Z is Q is selected from the group consisting of: —W— is
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Page/Page column 126
(2010/02/06)
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- Azaoxindole derivatives
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This invention relates to novel 4-, 5-, 6-, and 7-azaoxindole derivatives. The compounds are anti-inflammatory and analgesic agents and inhibitors of one or more of prostaglandin H2 synthase, 5-lipoxygenase and interleukin-1 biosynthesis. They are useful in the treatment of chronic inflammatory diseases, allergy, psoriasis, various bone diseases, and immune dysfunctions such as systemic lupus erythematosis.
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- Synthesis of substituted azaoxindoles for the preparation of aza-tenidap analogs
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The preparation of a set of eight azaoxindoles bearing substituents on the aromatic nucleus is outlined. These compounds were required for the preparation of aza-analogs of the anti-inflammatory oxindole tenidap. Two methods of synthesis were used, the fi
- Robinson, Ralph P.,Donahue, Kathleen M.,Son, Paul S.,Wagy, Steven D.
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p. 287 - 293
(2007/10/03)
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- Azaoxindole derivatives
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This invention relates to novel 4-, 5-, 6-, and 7-azaoxindole derivatives. The compounds are anti-inflammatory and analgesic agents and inhibitors of one or more of prostaglandin H2 synthase, 5-lipoxygenase and interleukin-1 biosynthesis. They are useful in the treatment of chronic inflammatory diseases, allergy, psoriasis, various bone diseases, and immune dysfunctions such as systemic lupus erythematosis.
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