Discovery of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives as c-Src kinase inhibitors for the treatment of acute ischemic stroke.
We synthesized a series of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives and evaluated their ability to inhibit c-Src kinase; 7-(2-amino-2-methylpropylamino)-5-cyclopropyl-2-(3,5-dimethoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 7o and 7-(2-amino-2-methylpropylamino)-2-(3,5-dimethoxyphenylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide 7f showed potent inhibitory activity. Compound 7f inhibited c-Src selectively and exhibited satisfactory central nervous system (CNS) penetration. Furthermore, 7f.HCl reduced the infarct volume in vivo in a rat middle cerebral artery (MCA) occlusion model when administrated intraperitoneally.
Mukaiyama
Harunobu
H
Central Research Laboratory, Kissei Pharmaceutical Company Lt, Nagano, Japan. harunobu_mukaiyama@pharm.kissei.co.jp
Nishimura
Toshihiro
T
Shiohara
Hiroaki
H
Kobayashi
Satoko
S
Komatsu
Yoshimitsu
Y
Kikuchi
Shinji
S
Tsuji
Eiichi
E
Kamada
Noboru
N
Ohnota
Hideki
H
Kusama
Hiroshi
H
D000818:Animals; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013055:Spectrophotometry, Infrared; D020521:Stroke / Q000188:drug therapy*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019061:src-Family Kinases