Discovery and structure-activity relationship of 2,6-disubstituted pyrazines, potent and selective inhibitors of protein kinase CK2.
We report the discovery and structure-activity relationship of 2,6-disubstituted pyrazines, which are potent and selective CK2 inhibitors. Lead compound 1 was identified, and derivatives were prepared to develop potent inhibitory activity. As a result, we obtained compound 7, which was the smallest unit that retained potency. Then, introducing an aminoalkyl group at the 6-position of the indazole ring resulted in improved efficacy in both enzymatic and cell-based CK2 inhibition assays. Moreover, compound 13 showed selectivity against other kinases and in vivo efficacy in a rat nephritis model. These results show that 2,6-disubstituted pyrazines have potential as therapeutic agents for nephritis.
Toray Industries, Inc., 10-1-6 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Nobuhiro_Fuchi@nts.toray.co.jp
Nobuhiro
N
Fuchi
Yosuke
Y
Iura
Hiroaki
H
Kaneko
Aiko
A
Nitta
Kazuharu
K
Suyama
Hiroshi
H
Ueda
Shinichi
S
Yamaguchi
Kazumi
K
Nishimura
Shigeo
S
Fujii
Yumiko
Y
Sekiya
Masateru
M
Yamada
Toshiya
T
Takahashi
D000818:Animals; D001665:Binding Sites; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003198:Computer Simulation; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D009393:Nephritis / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D047390:Casein Kinase II