A Novel Sphingosine-1-Phosphate Receptor 1 Antagonist Prevents the Proliferation and Relaxation of Vascular Endothelial Cells by Sphingosine-1-Phosphate
-
- Yonesu Kiyoaki
- Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd.
-
- Nakamura Tsuyoshi
- Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd.
-
- Mizuno Yumiko
- Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd.
-
- Suzuki Chie
- Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd.
-
- Nagayama Takahiro
- Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd.
-
- Satoh Susumu
- Daiichi Sankyo RD Associe Co., Ltd.
-
- Nara Futoshi
- Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd.
この論文をさがす
抄録
A sphingosine-1-phosphate receptor 1 (S1P1) antagonist is expected to be an anti-angiogenic compound; however, there are few reports that demonstrated that a S1P1 inhibitor improved the disease state in an angiogenic animal model. Since we determined that a prototype S1P1 antagonist was an in vivo angiogenesis inhibitor, we developed the derivatives to acquire more effective compounds. In this report, we show the S1P1 antagonistic activity of some representatives, especially compound 5 {sodium 4-[(4-butoxyphenyl)thio]-2′-[{4-[(heptylthio)methyl]-2-hydroxyphenyl}(hydroxy)methyl]biphenyl-3-sulfonate}. The IC50 values calculated from an intracellular cyclic AMP measurement assay and a [33P]sphingosine-1-phosphate (Sph-1-P)/S1P1 binding assay were 38 and 200 nM, respectively. A subtype specificity test for the other Sph-1-P receptors showed that compound 5 was the S1P1-directional antagonist. It also inhibited the proliferation, migration, and tube formation of human umbilical vein endothelial cells stimulated by Sph-1-P with the IC50 values of 18, 650, and 230 nM, respectively. A cytotoxicity assay concurrently performed with a tube formation assay supported the hypothesis that these biological effects were not due to its cytotoxicity. Furthermore, administration (10 mg/kg, intravenously) to anesthetized Sprague-Dawley rats inhibited Sph-1-P-induced hypotension by 100—90% for 30 min. This is presumably through the inhibition of Sph-1-P-induced vasorelaxation, mainly by the blocking of S1P1 and/or S1P3. Taken together, these results show that compound 5 is an inhibitor of in vitro and in vivo Sph-1-P signaling, and that it will be useful to elucidate the in vivo effect of Sph-1-P on vascular endothelial cells.
収録刊行物
-
- Biological & Pharmaceutical Bulletin
-
Biological & Pharmaceutical Bulletin 33 (9), 1500-1505, 2010
公益社団法人 日本薬学会
- Tweet
キーワード
詳細情報 詳細情報について
-
- CRID
- 1390282679603276160
-
- NII論文ID
- 130000322346
-
- NII書誌ID
- AA10885497
-
- ISSN
- 13475215
- 09186158
-
- NDL書誌ID
- 10796791
-
- 本文言語コード
- en
-
- データソース種別
-
- JaLC
- NDL
- Crossref
- CiNii Articles
-
- 抄録ライセンスフラグ
- 使用不可