title: 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.affiliation: Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: shigeki.kunikawa@astellas.com.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kunikawa
authors.affiliation: Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Mukoyoshi
authors.affiliation: Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Nagashima
authors.affiliation: Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tominaga
authors.affiliation: Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Chida
authors.affiliation: Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tasaki
authors.affiliation: Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Shirai
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015870:Gene Expression; D054879:Halogenation; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta
keywords: CYP3A4 time-dependent inhibition (TDI); P-glycoprotein (P-gp); Protein kinase C theta (PKCθ)