Optimization of 2,4-diamino-5-fluoropyrimidine derivatives as protein kinase C theta inhibitors with mitigated time-dependent drug-drug interactions and P-gp liability.

Abstract

Protein kinase C theta (PKCθ) plays a critical role in T cell signaling and has therapeutic potential for T cell-mediated diseases such as transplant rejection and rheumatoid arthritis. Here, a series of 2,4-diamino-5-fluoropyrimidine derivatives were prepared and evaluated for their inhibition of PKCθ. Of these compounds, 14f was found to exhibit potent PKCθ inhibitory activity and significantly weak CYP3A4 time-dependent inhibition (TDI) and P-glycoprotein (P-gp) liability.

• Authors: Shigeki Kunikawa, Akira Tanaka, Koichiro Mukoyoshi, Shinya Nagashima, Hiroaki Tominaga, Noboru Chida, Mamoru Tasaki, Fumiyuki Shirai
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 13 Pg. 3269-77 (Jul 01 2015) ISSN: 1464-3391 [Electronic] England
• PMID: 25982074 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Isoenzymes
• Protein Kinase Inhibitors
• Pyrimidines
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• PRKCQ protein, human
• Protein Kinase C
• Protein Kinase C-theta

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Cytochrome P-450 CYP3A (genetics, metabolism)
• Drug Interactions
• Drug Resistance, Neoplasm (drug effects)
• Gene Expression
• Halogenation
• Humans
• Isoenzymes (antagonists & inhibitors, genetics, metabolism)
• Microsomes, Liver (drug effects, metabolism)
• Protein Kinase C (antagonists & inhibitors, genetics, metabolism)
• Protein Kinase C-theta
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Signal Transduction
• Structure-Activity Relationship
• T-Lymphocytes (drug effects, metabolism, pathology)