A novel 2,4-diaminopyrimidine derivative as selective inhibitor of protein kinase C theta prevents allograft rejection in a rat heart transplant model

[Display omitted] Protein kinase C theta (PKCθ) plays a critical role in T cell signaling and is an attractive target for the treatment of T cell-mediated diseases such as transplant rejection and autoimmune disease. To identify PKCθ inhibitors, we focused on the 2,6-diamino-3-carbamoyl-5-cyanopyraz...

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Published inBioorganic & medicinal chemistry Vol. 26; no. 20; pp. 5499 - 5509
Main Authors Kunikawa, Shigeki, Tanaka, Akira, Takasuna, Yuji, Tasaki, Mamoru, Chida, Noboru
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier Ltd 01.11.2018
Elsevier
Subjects
Biochemistry & Molecular Biology
Chemistry
Chemistry, Medicinal
Chemistry, Organic
Immunosuppressant
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Physical Sciences
Protein kinase C theta (PKCθ)
Science & Technology
Selective
Protein kinase C theta (PKCθ)
Immunosuppressant
Selective
POTENT
THERAPY
Protein kinase C theta (PKC theta)
OPTIMIZATION
AEB071
PKC-THETA
DISCOVERY
SOTRASTAURIN
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Summary:[Display omitted] Protein kinase C theta (PKCθ) plays a critical role in T cell signaling and is an attractive target for the treatment of T cell-mediated diseases such as transplant rejection and autoimmune disease. To identify PKCθ inhibitors, we focused on the 2,6-diamino-3-carbamoyl-5-cyanopyrazine derivative 2, which exhibited moderate PKCθ inhibitory activity. Optimization of 2 identified the 2,4-diamino-5-cyanopyrimidine derivative 16c, which exhibited potent PKCθ inhibitory activity and showed good selectivity against other PKC isozymes. Compound 16c prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2018.09.029