Discovery of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives as c-Src kinase inhibitors for the treatment of acute ischemic stroke

被引：30

作者：

Mukaiyama, Harunobu ^{[1
]}

Nishimura, Toshihiro ^{[1
]}

Shiohara, Hiroaki ^{[1
]}

Kobayashi, Satoko ^{[1
]}

Komatsu, Yoshimitsu ^{[1
]}

Kikuchi, Shinji ^{[1
]}

Tsuji, Eiichi ^{[1
]}

Kamada, Noboru ^{[1
]}

Ohnota, Hideki ^{[1
]}

Kusama, Hiroshi ^{[1
]}

机构：

[1] Kissei Pharmaceut Co Ltd, Cent Res Lab, Nagano 3998304, Japan

来源：

CHEMICAL & PHARMACEUTICAL BULLETIN | 2007年 / 55卷 / 06期

关键词：

c-Src kinase; pyrazolo[1,5-a]pyrimidine; acute ischemic stroke; central nervous system penetration;

D O I：

10.1248/cpb.55.881

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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)-5methylpyrazolo[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 center dot HCl reduced the infarct volume in vivo in a rat middle cerebral artery (MCA) occlusion model when administrated intraperitoneally.

引用

页码：881 / 889

页数：9

共 25 条

[21] Cellular functions regulated by Src family kinases [J].

Thomas, SM ;

Brugge, JS .

ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 1997, 13 :513-609

[22] EVALUATION OF THE COMBINATION OF A TISSUE-TYPE PLASMINOGEN-ACTIVATOR, SUN9216, AND A THROMBOXANE A2 RECEPTOR ANTAGONIST, VAPIPROST, IN A RAT MIDDLE CEREBRAL-ARTERY THROMBOSIS MODEL [J].

UMEMURA, K ;

WADA, K ;

UEMATSU, T ;

NAKASHIMA, M .

STROKE, 1993, 24 (07) :1077-1081

[23] Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation [J].

Yamaguchi, H ;

Hendrickson, WA .

NATURE, 1996, 384 (6608) :484-489

[24] NMDA channel regulation by channel-associated protein tyrosine kinase Src [J].

Yu, XM ;

Askalan, R ;

Keil, GJ ;

Salter, MW .

SCIENCE, 1997, 275 (5300) :674-678

[25] VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain [J].

Zhang, ZG ;

Zhang, L ;

Jiang, Q ;

Zhang, RL ;

Davies, K ;

Powers, C ;

van Bruggen, N ;

Chopp, M .

JOURNAL OF CLINICAL INVESTIGATION, 2000, 106 (07) :829-838

← 1 2 3 →