Discovery of 2,4-diamino-5-cyanopyrimidine derivatives as protein kinase C theta inhibitors with mitigated time-dependent drug-drug interactions.

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. PKCθ inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the 2,4-diamino-5-cyanopyrimidine derivative 2 was a potent PKCθ inhibitor; however, it exhibited CYP3A4 time-dependent inhibition (TDI). Here, we report the structural modification of compound 2 into 34 focusing on mitigating CYP3A4 TDI. Compound 34 exhibited potent in vitro activity with mitigated CYP3A4 TDI and efficacy in vivo transplant model.

• Authors: Shigeki Kunikawa, Akira Tanaka, Yuji Takasuna, Mamoru Tasaki, Noboru Chida
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 27 Issue 5 Pg. 790-799 (03 01 2019) ISSN: 1464-3391 [Electronic] England
• PMID: 30704835 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Cytochrome P-450 CYP3A Inhibitors
• Diamines
• Protein Kinase Inhibitors
• Pyrimidines
• Protein Kinase C-theta
• Midazolam

Topics

• Animals
• Cytochrome P-450 CYP3A Inhibitors (chemical synthesis, pharmacokinetics, pharmacology)
• Diamines (chemical synthesis, pharmacokinetics, pharmacology)
• Drug Discovery
• Drug Interactions
• Female
• Graft Rejection (prevention & control)
• Haplorhini
• Humans
• Jurkat Cells
• Microsomes, Liver (metabolism)
• Midazolam (pharmacology)
• Molecular Structure
• Protein Kinase C-theta (metabolism)
• Protein Kinase Inhibitors (chemical synthesis, pharmacokinetics, pharmacology)
• Pyrimidines (chemical synthesis, pharmacokinetics, pharmacology)
• Rats, Inbred ACI
• Rats, Inbred Lew
• Rats, Sprague-Dawley
• Structure-Activity Relationship