Conclusion
In our effort to obtain antagonists of the ET receptors, rational design based on agonist structure played a crucial part in the strategy that led to SB 209670. In vivo pharmacological studies with SB 209670, both in our own laboratories and through the work of others, have done much to elucidate potential roles for ET in the etiology of disease and to establish the therapeutic potential of ET receptor antagonists. Hampered in our search for an orally effective agent by the poor bioavailability of SB 209670, intestinal permeability screening was used to discover SB 217242, an antagonist with excellent oral characteristics. The key contributions outlined above toward the design of SB 217242 emphasize the multi-disciplinary approach used in today’s drug discovery efforts.
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References
Arai, H., Hori, S., Aramori, I., Ohkubo, H., and Nakanishi, S., 1990, Cloning and expression of a cDNA encoding an endothelin receptor, Nature 348:730–732.
Barone, F. C, White, R. F, Elliott, J. D., Feuerstein, G. Z., and Ohlstein, E. H., 1995, The endothelin receptor antagonist SB 217242 reduces cerebral focal ischemic brain injury, J. Cardiovasc. Pharmacol. 26(Suppl. 3):S404–S407.
Bean, J. W., Peishoff, C. E., and Kopple, K. D., 1994, Conformations of cyclic pentapeptide endothelin receptor antagonists, Int. J. Peptide Protein Res. 44:223–232.
Brooks, D. P., DePalma, P. D., Gellai, M., Nambi, P., Ohlstein, E. H., Elliott, J. D., Gleason, J. G., and Ruffolo, R. R., Jr., 1994, Non-peptide endothelin receptor antagonists. III. Effect of SB 209670 and BQ 123 on acute renal failure in anesthetized dogs, J. Pharmacol. Exp. Ther. 271:769.
DeNucci, G., Thomas, R., D’Orleans-Juste, P., Antunes, E., Walder, C., Warner, T. D., and Vane, J. R., 1988, Pressor effects of circulating endothelin are limited by its removal from the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor, Proc. Natl. Acad. Sci. USA 85:9797–9800.
Douglas, S. A., Louden, C., Vickery-Clark, L. M., Storer, B. L., Hart, T., Feuerstein, G. Z., Elliott, J. D., and Ohlstein, E. H., 1994, A role for endogenous endothelin-1 in neointimal formation after rat carotid artery balloon angioplasty, Circ. Res. 75:190–197.
Ellens, H., Eddy, E. P., Lee, C.-P, Dougherty, P., Lago, A., Xiang, J.-N., Elliott, J. D., Cheng, H.-Y, Ohlstein, E., and Smith, P. L., 1997, In vitro permeability screening for identification of orally bioavailable endothelin receptor antagonists, Adv. Drug Delivery Rev. 23:99–109.
Elliott, J. D., Lago, M. A., Cousins, R. D., Gao, A., Leber, J. D., Erhard, K. F., Nambi, P., Elshourbagy, N. A., Kumar, C., Lee, J. A., Bean, J. W., DeBrosse, C. W., Eggleston, D. S., Brooks, D. P., Feuerstein, G., Ruffolo, R. R., Weinstock, J., Gleason, J. G., Peishoff, C. E., and Ohlstein, E. H., 1994, l,3-Diarylindan-2-carboxylic acids, potent and selective non-peptide endothelin receptor antagonists, J. Med. Chem. 37:1553–1557.
Elliott, J. D., Bryan, D. L., Nambi, P., and Ohlstein, E. H., 1996, A novel series of non-peptide endothelin receptor antagonists, in: Peptides: Chemistry, Structure and Biology (P. T. P. Kaumaya and R. S. Hodges, eds.), pp. 673–675, Mayflower Scientific, Kingswinford.
Estrada, V., Tellez, M. J., Moya, J., Fernandez-Durango, R., Egido, J., and Cruz, A. F., 1994, High plasma levels of endothelin-1 and atrial natriuretic peptide in patients with acute ischemic stroke, Am. J. Hypertens. 7:1085–1089.
Gellai, M., Jugus, M., Fletcher, T., DeWolf, R., and Nambi, P., 1994, Reversal of postischemic ARF with a selective ETA receptor antagonist in the rat, J. Clin. Invest. 93:900–906.
Hunt, J. T., 1992, SAR of endothelin deduced from monocyclic analogs, Drug News Perspect. 5:78–82.
Hunt, J. T., Lee, V. G., Stein, P. D., Hedberg, A., Liu, E. C.-K., McMullen, D., and Moreland, S., 1991, Structure-activity relationships of monocyclic endothelin analogs, Bio-Org. Med. Chem. Lett. 1:33–38.
Ihara, M., Noguchi, K., Saeki, T., Fukuroda, T., Tsuchida, S., Kimura, S., Fukami, T., Ishikawa, K., Nishikibe, M., and Yano, M., 1992, Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor, Life Sci. 50:247–255.
Krystek, S. R., Jr., Patel, P. S., Rose, P. M., Fisher, S. M., Kienzle, B. K., Lach, D. A., Liu, E. C., Lynch, J. S., Novotny, J., and Webb, M. L., 1994, Mutation of peptide binding site in transmembrane region of a G protein-coupled receptor accounts for endothelin receptor subtype selectivity, J. Biol. Chem. 269:12383–12386.
Lago, M. A., Luengo, J. I., Peishoff, C. E., and Elliott, J. D., 1996, Endothelin antagonists, Annu. Rep. Med. Chem. 31:81–90.
Lee, J. A., Elliott, J. D., Sutiphong, J. A., Friesen, W. J., Ohlstein, E. H., Stadel, J. M., Gleason, J. G., and Peishoff, C. E., 1994, Tyr-129 is important to the peptide ligand affinity and selectivity of human endothelin type A receptor, Proc. Natl, Acad. Sci. USA 91:7164–7168.
Lee, J. A., Sutiphong, J. A., Longton, E. D., Peishoff, C. E., Stadel, J. M., Kumar, C., Ohlstein, E. H., Gleason, J. G., and Elliott, J. D., 1995, Lysine 182 of endothelin B receptor modulates agonist selectivity and antagonist affinity: Evidence for the overlap of peptide and non-peptide ligand binding sites, Biochemistry 33:14543–14549.
Michael, J. R., and Markewitz, B. A., 1996, Endothelins and the lung, Am. J. Respir. Crit. Care Med. 154:555–581.
Nakajima, K., Kubo, S., Kumagaye, S., Nishio, H., Tsunemi, M., Inui, T., Kuroda, H., Chino, N., Watanabe, T. X., Kimura, T., and Sakakibara, S., 1989, Structure-activity relationship of endothelin: Importance of charged groups, Biochem. Biophys. Res. Commun. 163:424–429.
Ohlstein, E. H., Arleth, A., Bryan, H., Elliott, J. D., and Sung, C. P., 1992, The selective endothelin-A receptor antagonist BQ-123 antagonizes ET-1 mediated mitogenesis in vascular smooth muscle, Eur. J. Pharmacol. 225:347–350.
Ohlstein, E. H., Beck, G. R., Jr., Douglas, S. A., Nambi, P., Lago, A., Gleason, J. G., Ruffolo, R. R., Jr., Feuerstein, G., and Elliott, J. D., 1994a, Nonpeptide endothelin receptor antagonists. II. Pharmacological characterization of SB 209670, J. Pharmacol. Exp. Ther. 271:762–768.
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., Brooks, D. P., Weinstock, J., Feuerstein, G., Poste, G., Ruffolo, R. R. Jr.; Gleason, J. G. and Elliott, J. D., 1994b, SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist, Proc. Natl. Acad. Sci. USA 91:8052–8056.
Ohlstein, E. H., Nambi, P., Lago, A., Hay, D. W. P., Beck, G., Fong, K.-L., Eddy, E. P., Smith, P., Ellens, H., and Elliott, J. D., 1996, Nonpeptide endothelin receptor antagonists. VI: Pharmacological characterization of SB 217242, a potent and highly bioavailable endothelin receptor antagonist, J. Pharmacol. Exp. Ther. 276:609–615.
Panek, R. L., Major, T. C., Hingorani, G. P., Doherty, A. M, Taylor, D. G., and Rapundalo, S. T., 1992, Endothelin and structurally related analogs distinguish between endothelin receptor subtypes, Biochem. Biophys. Res. Commun. 183:566–571.
Ruffolo, R. R., Jr., 1995, Endothelin Receptors from the Gene to the Human, CRC Press, Boca Raton.
Sakurai, T., Yanagisawa, M., Takuwa, Y., Miyazaki, H., Kimura, S., Goto, K., and Masaki, T., 1990, Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor, Nature 348:732–735.
Strader, C. D., Sigal, I. S., Register, R. B., Candelore, M. R., Rands, E., and Dixon, R. A., 1987, Identification of residues required for ligand binding to the beta-adrenergic receptor, Proc. Natl. Acad. Sci. USA 84:4384–4388.
Strader, C. D., Sigal, I. S., Candelore, M. R., Rands, E., Hill, W. S., and Dixon, R. A., 1988, Conserved aspartic acid residues 79 and 113 of the beta-adrenergic receptor have different roles in receptor function, J. Biol. Chem. 263:10267–10271.
Tam, J. P., Liu, W., Zhang, J.-W., Galatino, M., Bertolero, F., Cristiani, C., Vaghi, F., and Castiglione, R. D., 1994, Alanine scan of endothelin: Importance of aromatic residues, Peptides 15:703–708.
Underwood, D. C., Bochnowicz, S., Osborn, R. R., Luttman, M. A., and Hay, D. W. P., 1997, Nonpeptide endothelin receptor antagonists. X. Inhibition of endothelin-1 and hypoxia-induced pulmonary pressor responses in the guinea pig by the endothelin receptor antagonist, SB 217242, J. Pharmacol. Exp. Ther. 283:1130–1137.
Warner, T. D., Allcock, G. H., Corder, R., and Vane, J. R., 1993, Use of the endothelin antagonists BQ 123 and PD 142893 to reveal three endothelin receptors mediating smooth muscle contraction and release of EDRF, Br. J. Pharmacol. 110:777–782.
Webb, M. L., and Meek, T. D., 1997, Inhibitors of endothelin, Med. Res. Rev. 17:17–67.
Wei, G. Z., Zhang, J., Sheng, S. L., Ai, H. X., Ma, J. C., and Lui, H. B., 1993, Increased plasma ET-1 in patients with acute cerebral infarction and actions on pial arterioles of rat, Chin. Med. J. 106:917–921.
Xu, D., Emoto, N., Giaid, A., Slaughter, C., Kaw, S., Wit, D. D., and Yanigasawa, M., 1994, ECE-1: A membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1, Cell 78:473.
Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui, Y., Yazaki, Y, Goto, K., and Masaki, T. A., 1988, A novel potent vasoconstrictor peptide produced by vascular endothelial cells, Nature 332:411–415.
Ziv, I., Fleminger, G., Dyaldetti, R., Achiron, A., Melamed, E., and Sokolovsky, M., 1992, Increased plasma endothelin-1 in acute ischemic stroke, Stroke 23:1014–1016.
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Elliott, J.D., Ohlstein, E.H., Peishoff, C.E., Ellens, H.M., Lago, M.A. (2002). Endothelin Receptor Antagonists. In: Borchardt, R.T., Freidinger, R.M., Sawyer, T.K., Smith, P.L. (eds) Integration of Pharmaceutical Discovery and Development. Pharmaceutical Biotechnology, vol 11. Springer, Boston, MA. https://doi.org/10.1007/0-306-47384-4_6
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