SB-209670, A RATIONALLY DESIGNED POTENT NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONIST

被引：177
作者：
OHLSTEIN, EH
NAMBI, P
DOUGLAS, SA
EDWARDS, RM
GELLAI, M
LAGO, A
LEBER, JD
COUSINS, RD
GAO, AM
FRAZEE, JS
PEISHOFF, CE
BEAN, JW
EGGLESTON, DS
ELSHOURBAGY, NA
KUMAR, C
LEE, JA
YUE, TL
LOUDEN, C
BROOKS, DP
WEINSTOCK, J
FEUERSTEIN, G
POSTE, G
RUFFOLO, RR
GLEASON, JG
ELLIOTT, JD
机构：
[1] SMITHKLINE BEECHAM PHARMACEUT,DEPT MED CHEM,KING OF PRUSSIA,PA 19406
[2] SMITHKLINE BEECHAM PHARMACEUT,DEPT PHARMACOL SCI,KING OF PRUSSIA,PA 19406
[3] SMITHKLINE BEECHAM PHARMACEUT,DEPT MOLEC GENET,KING OF PRUSSIA,PA 19406
[4] SMITHKLINE BEECHAM PHARMACEUT,DEPT MACROMOLEC SCI,KING OF PRUSSIA,PA 19406
[5] SMITHKLINE BEECHAM PHARMACEUT,DEPT PHYS & STRUCT CHEM,KING OF PRUSSIA,PA 19406
来源：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 1994年 / 91卷 / 17期
关键词：
D O I：
10.1073/pnas.91.17.8052
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
An extremely potent and highly specific nonpeptide, subnanomolar endothelin (ET) receptor antagonist, SB 209670, has been synthesized and characterized. SB 209670, which was rationally designed using conformational models of ET-1, selectively inhibits binding of I-125-labeled ET-1 to cloned human ET receptor subtypes ET(A) and ET(B) (K-i = 0.2 and 18 nM, respectively). SB 209670 produces concentration-dependent inhibition of ET-1-mediated vasoconstriction in isolated vascular tissues and in vivo following either intravenous or intraduodenal administration. SB 209670 produces a dose-dependent reduction in blood pressure in hypertensive rats, protects from ischemia-induced neuronal degeneration in a gerbil stroke model, and attenuates neointima formation following rat carotid artery balloon angioplasty. SB 209670 will be useful in characterizing and classifying the physiological and pathophysiological effects of ET.
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页码：8052 / 8056
页数：5
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