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

Shigeki Kunikawa; Akira Tanaka; Yuji Takasuna; Mamoru Tasaki; Noboru Chida

doi:10.1016/j.bmc.2019.01.019

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

Bioorg Med Chem. 2019 Mar 1;27(5):790-799. doi: 10.1016/j.bmc.2019.01.019. Epub 2019 Jan 23.

Authors

Shigeki Kunikawa¹, Akira Tanaka², Yuji Takasuna², Mamoru Tasaki², Noboru Chida²

Affiliations

¹ Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: [email protected].
² Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.

PMID: 30704835
DOI: 10.1016/j.bmc.2019.01.019

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.

Keywords: CYP3A4 time-dependent inhibition (TDI); Protein kinase C theta (PKCθ); Transplant rejection.

MeSH terms

Animals
Cytochrome P-450 CYP3A Inhibitors / chemical synthesis
Cytochrome P-450 CYP3A Inhibitors / pharmacokinetics
Cytochrome P-450 CYP3A Inhibitors / pharmacology
Diamines / chemical synthesis
Diamines / pharmacokinetics
Diamines / 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
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology*
Rats, Inbred ACI
Rats, Inbred Lew
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

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