960040-60-2Relevant academic research and scientific papers
Identification, characterization and initial hit-to-lead optimization of a series of 4-arylamino-3-pyridinecarbonitrile as protein kinase C theta (PKCθ) inhibitors
Cole, Derek C.,Asselin, Magda,Brennan, Agnes,Czerwinski, Robert,Ellingboe, John W.,Fitz, Lori,Greco, Rita,Huang, Xinyi,Joseph-McCarthy, Diane,Kelly, Michael F.,Kirisits, Matthew,Lee, Julie,Li, Yuanhong,Morgan, Paul,Stock, Joseph R.,Tsao, Désirée H. H.,Wissner, Allan,Yang, Xiaoke,Chaudhary, Divya
experimental part, p. 5958 - 5963 (2009/10/09)
The protein kinase C (PKC) family of serine/threonine kinases is implicated in a wide variety of cellular processes. The PKC theta (PKCθ) isoform is involved in TCR signal transduction and T cell activation and regulates T cell mediated diseases, including lung inflammation and airway hyperresponsiveness. Thus inhibition of PKCθ enzyme activity by a small molecule represents an attractive strategy for the treatment of asthma. A PKCθ high-throughput screening (HTS) campaign led to the identification of 4-(3-bromophenylamino)-5- (3,4-dimethoxyphenyl)-3-pyridinecarbonitrile 4a, a low μM ATP competitive PKCθ inhibitor. Structure based hit-to-lead optimization led to the identification of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-ylamino)-3- pyridinecarbonitrile 4p, a 70 nM PKCθ inhibitor. Compound 4p was selective for inhibition of novel PKC isoforms over a panel of 21 serine/threonine, tyrosine, and phosphoinositol kinases, in addition to the conventional and atypical PKCs, PKCβ, and PKCζ, respectively. Compound 4p also inhibited IL-2 production in antiCD3/anti-CD28 activated T cells enriched from splenocytes.
Substituted Cyanopyridines as protein kinase inhibitors
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Page/Page column 19, (2008/06/13)
The present teachings provide compounds of formula I and their pharmaceutically acceptable salts, hydrates, and esters, wherein R1, R2, and X are as defined herein. The present teachings also provide methods of making the compounds of formula I, and methods of treating autoimmune and inflammatory diseases by administering a therapeutically effective amount of a compound or compounds of formula I to a mammal including a human.
