SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist

Eliot H. Ohlstein; Ponnal Nambi; Stephen A. Douglas; Richard M. Edwards; Miklos Gellai; Amparo Lago; Jack D. Leber; Russell D. Cousins; Aiming Gao; James S. Frazee; Catherine E. Peishoff; John W. Bean; Drake S. Eggleston; Nabil A. Elshourbagy; Chandrika Kumar; Jonathan A. Lee; Tian Li Yue; Calvert Louden; David P. Brooks; Joseph Weinstock; Giora Feuerstein; George Poste; Robert R. Ruffolo; John G. Gleason; John D. Elliott

doi:10.1073/pnas.91.17.8052

SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist

Eliot H. Ohlstein, Ponnal Nambi, Stephen A. Douglas, Richard M. Edwards, Miklos Gellai, Amparo Lago, Jack D. Leber, Russell D. Cousins, Aiming Gao, James S. Frazee, Catherine E. Peishoff, John W. Bean, Drake S. Eggleston, Nabil A. Elshourbagy, Chandrika Kumar, Jonathan A. Lee, Tian Li Yue, Calvert Louden, David P. Brooks, Joseph WeinstockGiora Feuerstein, George Poste, Robert R. Ruffolo, John G. Gleason, John D. Elliott

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Abstract

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 ¹²⁵I-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.

Original language	English (US)
Pages (from-to)	8052-8056
Number of pages	5
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	91
Issue number	17
DOIs	https://doi.org/10.1073/pnas.91.17.8052
State	Published - Aug 16 1994
Externally published	Yes

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Ohlstein, E. H., Nambi, P., Douglas, S. A., Edwards, R. M., Gellai, M., Lago, A., Leber, J. D., Cousins, R. D., Gao, A., Frazee, J. S., Peishoff, C. E., Bean, J. W., Eggleston, D. S., Elshourbagy, N. A., Kumar, C., Lee, J. A., Yue, T. L., Louden, C., Brooks, D. P., ... Elliott, J. D. (1994). SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist. Proceedings of the National Academy of Sciences of the United States of America, 91(17), 8052-8056. https://doi.org/10.1073/pnas.91.17.8052

Ohlstein, EH, Nambi, P, Douglas, SA, Edwards, RM, Gellai, M, Lago, A, Leber, JD, Cousins, RD, Gao, A, 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 1994, 'SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist', Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 17, pp. 8052-8056. https://doi.org/10.1073/pnas.91.17.8052

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title = "SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist",

abstract = "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 125I-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.",

author = "Ohlstein, {Eliot H.} and Ponnal Nambi and Douglas, {Stephen A.} and Edwards, {Richard M.} and Miklos Gellai and Amparo Lago and Leber, {Jack D.} and Cousins, {Russell D.} and Aiming Gao and Frazee, {James S.} and Peishoff, {Catherine E.} and Bean, {John W.} and Eggleston, {Drake S.} and Elshourbagy, {Nabil A.} and Chandrika Kumar and Lee, {Jonathan A.} and Yue, {Tian Li} and Calvert Louden and Brooks, {David P.} and Joseph Weinstock and Giora Feuerstein and George Poste and Ruffolo, {Robert R.} and Gleason, {John G.} and Elliott, {John D.}",

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doi = "10.1073/pnas.91.17.8052",

language = "English (US)",

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AU - Ohlstein, Eliot H.

AU - Nambi, Ponnal

AU - Douglas, Stephen A.

AU - Edwards, Richard M.

AU - Gellai, Miklos

AU - Lago, Amparo

AU - Leber, Jack D.

AU - Cousins, Russell D.

AU - Gao, Aiming

AU - Frazee, James S.

AU - Peishoff, Catherine E.

AU - Bean, John W.

AU - Eggleston, Drake S.

AU - Elshourbagy, Nabil A.

AU - Kumar, Chandrika

AU - Lee, Jonathan A.

AU - Yue, Tian Li

AU - Louden, Calvert

AU - Brooks, David P.

AU - Weinstock, Joseph

AU - Feuerstein, Giora

AU - Poste, George

AU - Ruffolo, Robert R.

AU - Gleason, John G.

AU - Elliott, John D.

PY - 1994/8/16

Y1 - 1994/8/16

N2 - 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 125I-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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SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist

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