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Endothelin Receptor Antagonists

  • Chapter
Endothelin and Its Inhibitors

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 152))

Abstract

The earliest reported endothelin (ET) receptor antagonists were peptide in nature and arose structurally from relatively minor modifications to endothelin-1 (ET-1) (Spinella 1991). The most significant early departure from this paradigm came with the discovery of BE-18257B, a competitive and selective endothelin-A (ETA) receptor antagonist isolated from the fermentation products of Streptomyces misakiensis (Ihara 1991). BE-18257B is a cyclic pentapeptide, cyclo(D-Trp-D-Glu-Ala-D-Allo-Ile-Leu), which binds selectively to ETA receptors with an IC50 of 1.4 μmol/l (porcine aortic smooth muscle cells) and functionally antagonizes ET-1 induced vasoconstriction in the rabbit iliac artery with a pA2 of 5.9. Shortly after the discovery of BE-18257B, a similar series of cyclic pentapeptides was identified from a strain of Streptomyces (Miyata 1992). The most potent compound in this series, WS-7338B, is structurally identical to BE-18257B. In vivo evaluation in the spontaneously hypertensive rat showed that pretreatment with 10 mg/kg of WS-7338B reduced the pressor effect of ET-1 (3.2μg/kg; 55% inhibition), while leaving unaffected the initial depressor response, the pressor and depressor responses being mediated by ETA and endothelin-B (ETB) receptors, respectively. While the selectivity profile of BE-18257B is attractive, the moderate activity and poor water solubility of the compound have restricted its use as a tool in pharmacological studies. Chemical modification of BE-18257B led to a series of antagonists which not only exhibit higher affinity for the ETA receptor but also possess good solubility in aqueous solution.

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References

  • Anzali S, Mederski WWKR, Osswald M, Dorsch D (1998) 1. Endothelin antagonists: search for surrogates of methylenedioxyphenyl by means of a Kohonen Neural network. Bioorg Med Chem Lett 8:11–16

    Article  PubMed  CAS  Google Scholar 

  • Aramori I, Nirei H, Shoubo M, Sogabe K, Nakamura K, Kojo H, Notsu Y, Ono T, Nakanishi S (1993) Subtype selectivity of a novel endothelin antagonist, FR139317, for the two endothelin receptors in transfected Chinese hamster ovary cells. Mol Pharmacol 43:127–131

    PubMed  CAS  Google Scholar 

  • Bean JW, Peishoff CE, Kopple KD (1994) Conformations of cyclic pentapeptide endothelin receptor antagonists. Int J Peptide Protein Res 44:223–232

    Article  CAS  Google Scholar 

  • Beyer ME, Slesak G, Brehm BR, Hoffmaeister HM (1998) Hemodynamic and inotropic effects of the endothelin A antagonist BQ-610 in vivo. J Cardiovasc Pharmacol 31 [Suppl 1]:S258–S261

    Article  PubMed  CAS  Google Scholar 

  • Bogusky MJ, Brady SF, Sisko JT, Nutt RF, Smith GM (1994) Synthesis and solution conformation of c(Trp-D-Cys(SO3 -Na+)-Pro-D-Val-Leu), a potent endothelin-A receptor antagonist. Int J Peptide Protein Res 42:194–203

    Article  Google Scholar 

  • Brandbury RH, Bath C, Butlin RJ, Dennis M, Heys C, Hunt SJ, James R, Mortlock AA, Sumner NF, Tang EK, Telford B, Whiting E, Wilson C (1997) New non-peptide endothelin-A receptor antagonists: Synthesis, biological properties, and structureactivity relationships of 5-(dimethylamino)-N-pyridyl-, -N-pyrimidinyl, -N-pyridazinyl, and -Af-pyrazinyl-1-naphthalenesulfonamides. J Med Chem 40:996–1004

    Article  Google Scholar 

  • Breu V, Clozel M, Burri K, Hirth G, Neidhart W, Ramuz H (1996) In vitro characterization of Ro 46-8443, the first non-peptide antagonist selective for the endothelin ETB receptor. FEBS Lett 383:37–41

    Article  PubMed  CAS  Google Scholar 

  • Breu V, Hashido K, Broger C, Miyamoto C, Furuichi Y, Kalina B, Loffler B-M, Ramuz H, Clozel M (1995) Separable binding sites for the natural agonist endothelin-1 and the non-peptide antagonist bosentan on human endothelin-A receptors. Eur J Biochem 231:226–270

    Article  Google Scholar 

  • Cardell LO, Uddman R, Edvinsson L (1993) A novel ETA-receptor antagonist, FR139317, inhibits endothelin-induced contractions of guinea-pig pulmonary arteries, but not trachea. Br J Pharmacol 108:448–452

    Article  PubMed  CAS  Google Scholar 

  • Chan MF, Raju B, Kois A, Castillo RS, Verner EJ, Wu C, Hwang E, Okun I, Stavros F, Balaji VN (1996) Halogen substitution at the isoxazole ring enhances the activity of N-(Isoxazolyl)sulfonamide endothelin antagonists. Bioorg Med Chem Lett 6(20):2393–2398

    Article  CAS  Google Scholar 

  • Clozel M, Breu V (1996) The role of ETB receptors in normotensive and hypertensive rats as revealed by the non-peptide selective ETB receptor antagonist Ro 46–8443. FEBS Lett 383:42–45

    Article  PubMed  CAS  Google Scholar 

  • Clozel M, Breau V, Gray GA, Kalina B, Loffler B-M, Burri K, Cassal J-M, Hirth G, Muller M, Neidhart W, Ramuz H (1994) Pharmacological characterization of bosentan, a new potent orally active non-peptide endothelin receptor antagonist. J Pharmacol Exp Ther 270:228–235

    PubMed  CAS  Google Scholar 

  • Clozel M, Breau V, Burri K, Cassal J-M, Fischli W, Gray GA, Hirth G, Loffler B-M, Muller M, Neidhart W, Ramuz H (1993) Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature (London) 365:759–761

    Article  CAS  Google Scholar 

  • Cody WL, He JX, Reily MD, Haleen SJ, Walker DM, Reyner EL, Stewart BH, Doherty AM (1997) Design of a potent combined pseudopeptide endothelin-A/endothelin-B receptor antagonist, Ac-DBhgl6-Leu-Asp-Ile-[NMe]Ile-Trp21 (PD 156252): Examination of its pharmacokinetic and spectral properties. J Med Chem 40(14):2228–2240

    Article  PubMed  CAS  Google Scholar 

  • Cody WL, Doherty AM, He JX, DePue PL, Waite LA, Topliss JG, Haleen SJ, LaDouceur D, Flynn MA, Hill KE, Reynolds EE (1993) The rational design of an highly potent combined ETA and ETB receptor antagonist (PD145065) and related analogues. Med Chem Res 3:154–162

    CAS  Google Scholar 

  • Cody WL, Doherty AM, He JX, DePue, PL, Rapundalo ST, Higorani GA, Major TC, Panek RL, Dudley D, Haleen SJ, LaDouceur D, Hill KE, Flynn MA, Reynolds EE (1992a) Design of a functional hexapeptide antagonist of endothelin. J Med Chem 35:3301–3303

    Article  PubMed  CAS  Google Scholar 

  • Cody WL, Doherty AM, He JX,Topliss JG, Haleen SJ, LaDouceur D, Flynn MA, Hill KE, Reynolds EE (1992b) Structure-activity relationships in the C-terminus of endothelin-1 (ET-l).The discovery of potent antagonists. In: Schneider CH,Eberle AN (eds) Peptides 1992: Proceedings of the Twenty-Second European American Peptide Symposium. ESCOM Science: Leiden, The Netherlands, pp 687–688

    Google Scholar 

  • Davenport AP, Kuc RE, Fitzgerald F, Maguire JJ, Berryman K, Doherty AM (1994) [125I]-PD151241: a selective radioligand for human ETA receptors. Br J Pharmacol 111:4–6

    Article  PubMed  CAS  Google Scholar 

  • Doherty A, Patt W, Reisdorph B, Repine J, Walker D, Flynn M, Welch K, Reynolds E, Haleen S (1996) Design and pharmacological evaluation of a series of non-peptide endothelin ETA selective and ETA/ETB receptor antagonists. In: Yamazake M (ed) Med Chem: Today Tomorrow, Proc AFMC Int Med Chem Symp. Blackwell Science Ltd, London, UK, pp 255–261

    Google Scholar 

  • Doherty AM, Cody WL, DePue PL, He JX, Waite LA, Leonard DM, Leitz NL, Dudley D, Rapundalo ST, Higorani GA, Haleen SJ, LaDouceur D, Hill KE, Flynn MA, Reynolds EE (1993a) Structure-activity relationships of C-terminal endothelin hexapeptide antagonists. J Med Chem 36:2585–2594

    Article  PubMed  CAS  Google Scholar 

  • Doherty AM, Cody WL, He JX, DePue PL, Leonard DM, Dunbar JB, Hill KE, Flynn MA, Reynolds EE (1993b) Design of C-terminal peptide antagonists of endothelin. Structure-activity relationship of ET-1[16–21, D-Hisl6]. Bioorg Med Chem Lett 3:497–502

    Article  CAS  Google Scholar 

  • Douglas SA, Nambi P, Gellai M, Luengo JI, Xiang J-N, Brooks DP, Ruffolo RR Jr, Elliott JD, Ohlstein EH (1998) Pharmacologic characterization of the novel, orally available endothelin-A-selective antagonist SB 247083, Pharmacologic characterization of the novel, orally available endothelin-A-selective antagonist SB 247083. J of Cardiovase Pharmacol 31 [Suppl 1]:S273-S276

    Article  CAS  Google Scholar 

  • Douglas SA, Louden C, Vickery-Clark LM, Storer BL, Hart T, Feuerstein G, Elliott JD, Ohlstein EH (1994) A role for endogenous endothelin-1 in neointimal formation after rat carotid artery balloon angioplasty. Circ Res 75:190–197

    Article  PubMed  CAS  Google Scholar 

  • Elliott JD, Bryan DL, Nambi P, Ohlstein EH (1996) A Novel Series of Non-Peptide Endothelin Receptor Antagonists In: Kaumana PTP, Hodges RD (eds) Peptides: chemistry, structure and biology. Mayflower Scientific Ltd, Kingswinford, pp 673–676

    Google Scholar 

  • Elliott JD, Lago MA, Cousins RD, Gao A, Leber JD, Erhart KF, Nambi P, Elshourbagy NA, Kumar C, Lee JA, Bean JW, DeBrosse CW, Eggleston DS, Brooks DP, Feuerstein G, Ruffolo RR Jr, Weinstock J, Gleason JG, Peishoff CE, Ohlstein EH (1994) l,3-Diarylindane-2-carboxylic acids, potent and selective non-peptide endothelin receptor antagonists. J Med Chem 37:1553–1557

    Article  PubMed  CAS  Google Scholar 

  • Endo S, Inooka H, Ishibashi Y, Kitada C, Mizuta E, Fujino M (1989) Solution conformation of endothelin determined by nuclear magnetic resonance and distance geometry. FEBS Lett 257:149–154

    Article  PubMed  CAS  Google Scholar 

  • Fruh T, Saika H, Svensson L, Pitterna T, Sakaki J, Okada T, Urade Y, Oda K, Fujutani Y, Takimoto M, Yamamura T, Inui T, Makatani M, Takai M, Umemura I, Teno N, Toh H, Hayakawa K, Murata T (1996) IRL 2500: A potent ETB selective endothelin antagonist. Bioorg Med Chem Lett 6(20):2323–2328

    Article  CAS  Google Scholar 

  • Fujimoto M, Mihara S, Nakajima S, Ueda M, Nakamura M, Sakurai K (1992) A novel non-peptide endothelin antagonist isolated from bayberry, Myrica cerifera. FEBS Lett 305:41–44

    Article  PubMed  CAS  Google Scholar 

  • Gellai M, Jugus M, Fletcher T, De Wolf R, Nambi P (1994) Reversal of post-ischemic acute renal failure with a selective endothelin A receptor antagonist in the rat. J Clin Invest 93:900–906

    Article  PubMed  CAS  Google Scholar 

  • He JX, Cody WL, Flynn MA, Welch KM, Reynolds EE, Doherty AM (1995) RES-701–1, synthesis and a re-evaluation of its effects on the endothelin receptors. Bioorg Med Chem Lett 5(6):621–626

    Article  CAS  Google Scholar 

  • Hingorani G, Major T, Panek R, Flynn M, Reynolds E, He X, Cody W, Doherty A, Rapundalo S (1992) In vitro pharmacology of a nonselective ETA/ETB endothelin receptor antagonist, PD 142893 (Ac-(β-phenyl)D-Phe-Leu-Asp-Ile-Ile-Trp trifluoroacetate). FASEB J 6(Part 1, No.4):392

    Google Scholar 

  • Ihara M, Noguchi K, Saeki T, Fukuroda T, Tsuchida S, Fukami T, Ishikawa K, Nishikibe M, Yano M (1992) Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor. Life Sci 50:247–255

    Article  PubMed  CAS  Google Scholar 

  • Ihara M, Fukuroda T, Saeki T, Nishikibe M, Kojiri K, Suda H, Yano M (1991) An endothelin receptor (ETA) antagonist isolated from Streptomyces misakiensis. Biochem Biophys Res Commun 178:132–137

    Article  PubMed  CAS  Google Scholar 

  • Ishikawa K, Ihara M, Noguchi K, Mase T, Mino N, Saeki T, Fukuroda T, Fukami T, Ozaki S, Nagase T, Nishikibe M, Yano M (1994) Biochemical and pharmacological profile of a potent and selective endothelin-B receptor antagonist, BQ-788. Proc Natl Acad Sci USA 91:4892–4896

    Article  PubMed  CAS  Google Scholar 

  • Ishikawa K, Fukami T, Nagase T, Fujita K, Hayama T, Niiyama K, Mase T, Ihara M, Yano M (1992) Cyclic pentapeptide endothelin antagonists with high ETA selectivity. Potency- and solubility-enhancing modifications. J Med Chem 35:2139–2142

    Article  PubMed  CAS  Google Scholar 

  • Jae H-S, Winn M, Dixon, DB, Marsh KC, Nguyen B, Opgenorth TJ, von Geldern TW (1997) Pyrrolidine-3-carboxylic acids as endothelin antagonists. 2. Sulfonamidebased ETA/ETB mixed antagonists. J Med Chem 40:3217–3227

    Article  PubMed  CAS  Google Scholar 

  • Keenan RM, Weinstock J, Finkelstein JA, Franz RG, Gaitanopoulos DE, Girard GR, Hill DT, Morgan TM, Samanen JM, Hempel J, Eggleston DS, Aiyar N, Griffin E, Ohlstein EH, Stack EJ, Weidley EF, Edwards RM (1992) Imidazole-5-acrylic acids: potent nonpeptide angiotensin II receptor antagonists designed using a novel peptide pharmacophore model. J Med Chem 35:3858–3872

    Article  PubMed  CAS  Google Scholar 

  • Kiowski W, Sutsch G, Hunziker P, Muller P, Kim J, Oechslin E, Schmitt R, Jones R, Bertel O (1995) Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 346:732–736

    Article  PubMed  CAS  Google Scholar 

  • Kitada C, Ohtaki T, Masuda Y, Masuo Y, Nomura H, Asami T, Matsumoto Y, Satou M, Fujino M (1993) Design and synthesis of ETA receptor antagonists and study of ETA receptor distribution. J Cardiovasc Pharmacol 22 [Suppl 8]:S128-S131

    Article  PubMed  CAS  Google Scholar 

  • Krum H, Viskoper RJ, Lacourciere Y, Budde M, Charlon V (1998) The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. N Engl J Med 338(12):784–790

    Article  PubMed  CAS  Google Scholar 

  • Kryste SR Jr, Bassolino DA, Bruccoleri RE, Hunt JT, Porubcan MA, Wandler CF, Anderson NH (1992) Solution conformation of a cyclic pentapeptide endothelin antagonist. Comparison of structures obtained from constrained dynamics and conformational search. FEBS Lett 299:255–261

    Article  Google Scholar 

  • LaDouceur DM, Davis LS, Keiser JA, Doherty AM, Cody WL, He FX, Haleen SJ (1992) Effects of the endothelin receptor antagonist PD 142893 (Ac-(β-phenyl)D-Phe-Leu-Asp-Ile-Ile-Trp trifluoroacetate) on endothelin-1 (ET-1) induced vasodilation and vasoconstriction in regional arterial beds of the anesthetized rat. FASEB J 6(Part 1, No.4):390

    Google Scholar 

  • Liu G, Henry KJ, Szczepankiewicz BG, Winn M, Kozmina NS, Boyd SA, Wasicak J, von Geldern TW, Wu-Wong JR, Chiou WJ, Dixon DB, Nguyen B, Marsh KC, Opgenorth TJ (1998) Pyrrolidine-3-carboxylic acids as endothelin antagonists. 3. Discovery of a potent, 2-nonaryl, highly selective ETA antagonist (A-216546). J Med Chem 41(17):3261–3275

    Article  PubMed  CAS  Google Scholar 

  • Maggi CA, Giuliani S, Patacchini R, Santicioli P, Giachetti A, Meli A (1989) The Cterminal hexapeptide, endothelin(16–21), discriminates between different receptors. Eur J Pharmacol 174:23–31

    Article  PubMed  CAS  Google Scholar 

  • Mederski WWKR, Osswald M, Dorsch D, Anzali S, Christadler M, Schmitges C-J, Wilm C (1998) 2. Endothelin antagonists: Evaluation of 2,1,3-benzothiadiazole as a methylenedioxyphenyl bioisoster. Bioorg Med Chem Lett 8:17–22

    Article  PubMed  CAS  Google Scholar 

  • Mihara S, Nakajima S, Matumura S, Kohnoike T, Fujimoto M (1994) Pharmacological characterization of a potent nonpeptide endothelin receptor antagonist 97–139. J Pharmacol Exp Ther 268:1122–1128

    PubMed  CAS  Google Scholar 

  • Mihara S, Fujumoto M (1993a) The endothelin ETA receptor-specific effect of 50–235, a non-peptide endothelin antagonist. Eur J Pharmacol Mol Pharmacol 246:33–38

    Article  CAS  Google Scholar 

  • Mihara S, Sakurai K, Nakamura M, Konoike T, Fujimoto M (1993b) Structure-activity relationships of an endothelin ETA receptor antagonist, 50–235, and its derivatives. Eur J Pharmacol Mol Pharmacol 247:219–221

    Article  CAS  Google Scholar 

  • Mills RG, O’Donoghue SI, Smith R, King GF (1992) Solution structure of endothelin-3 determined using NMR spectroscopy. Biochemistry 31:5640–5645

    Article  PubMed  CAS  Google Scholar 

  • Mills RG, Atkins AR, Harvey T, Junius FK, Smith R, King GF (1991) Conformation of sarafotoxin-6b in aqueous solution determined by NMR spectroscopy and distance geometry. FEBS Lett 282:247–252

    Article  PubMed  CAS  Google Scholar 

  • Miyata S, Fukami N, Neya M, Takase S, Kiyoto S (1992a) WS-7338, new endothelin receptor antagonists isolated from Streptomyces sp. No. 7338. III. Structure of WS-7338 A, B, C and D and total synthesis of WS-7338, B. J Antibiot 45:788–791

    Article  CAS  Google Scholar 

  • Miyata S, Ohata N, Murai H, Masui Y, Ezaki M, Takase S, Nishikawa M, Kiyoto S, Okuhara M, Kohsaka M (1992b) WS009 A and B, new endothelin receptor antagonists isolated from Streptomyces sp. No. 89009.I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities. J Antibiot 45: 1029–1040

    Article  PubMed  CAS  Google Scholar 

  • Miyata S, Hashimoto M, Fujie K, Shouho M, Sogabe K, Kiyoto S, Okuhara M, Kohsaka M (1992c) WS009 A and B, new endothelin receptor antagonists isolated from Streptomyces sp. No. 89009. II. Biological characterization and pharmacological characterization of WS009 A and B. J Antibiot 45:1041–1046

    Article  PubMed  CAS  Google Scholar 

  • Morishita Y, Chiba S, Tsukuda E, Tanaka T, Ogawa T, Yamasaki M, Yoshida M, Kawamoto I, Matsuda Y (1994) RES-701–1, a novel and selective endothelin type B receptor antagonist produced by Streptomyces sp. RE-701. I. Characterization of producing strain, fermentation, isolation, physico-chemical and biological properties. J Antibiotics 47:269–275

    Article  CAS  Google Scholar 

  • Mortlock AA, Bath C, Butlin RJ, Heys C, Hunt SJ, Reid AC, Sumner NF, Tang EK, Whiting E, Wilson C, Wright ND (1997) N-Methyl-2-[4-(2-methylpropyl) phenyl]-3-(3-methoxy-5-methylpyrazin-2-ylsulfamoyl)benzamide; One of a class of novel benzenesulphonamides which are orally-active, ETA-selective endothelin antagonists. Bioorg Med Chem Lett 7(11):1399–1402

    Article  CAS  Google Scholar 

  • Murugesan N, Gu Z, Lee V, Webb ML, Liu EC-K, Hermsmeier M, Hunt JT (1995) Design and synthesis of nonpeptidal endothelin receptor antagonists based on the structure of a cyclic pentapeptide. Bioorg Med Chem Lett 5:253–258

    Article  CAS  Google Scholar 

  • Neidhart W, Breu V, Burri K, Clozel M, Hirth G, Klinkhammer U, Giller T, Ramuz H (1997) Discovery of Ro 48–5695: A potent endothelin receptor antagonist optimized from Bosentan. Bioorg Med Chem Lett 7:2223–2228

    Article  CAS  Google Scholar 

  • Ohashi H, Akiyama H, Nishikori K, Mochizuki J-I (1992) Asterric acid, a new endothelin binding inhibitor. J Antibiot 45:1684–1685

    Article  PubMed  CAS  Google Scholar 

  • Ohlstein EH, Nambi P, Douglas SA, Edwards RM, Gellai M, Lago MA, Leber JD, Cousins RD, Gao A, Peishoff CE, Bean JW, Eggleston DS, Elshourbagy NA, Kumar C, Lee JA, Brooks DP, Ruffolo RR Jr, Feuerstein G, Weinstock J, Gleason JG, Elliott JD (1994) SB 209670, a rationally designed potent non-peptide endothelin receptor antagonist. Proc Natl Acad Sci USA 91:8052–8056

    Article  PubMed  CAS  Google Scholar 

  • Ohlstein EH, Vickery-Clark LM, Storer BL, Douglas SA (1993) Antihypertensive effects of the endothelin receptor antagonist BQ-123 in conscious spontaneously hypertensive rats. J Cardiovasc Pharmacol 22 [Suppl 8]:S321-S324

    Article  PubMed  CAS  Google Scholar 

  • Ohlstein EH, Arleth A, Bryan H, Elliott JD, Sung CP (1992) The selective endothelin-A receptor antagonist BQ-123 antagonizes ET-1 mediated mitogenesis in vascular smooth muscle. Eur J Pharmacol 225:347–350

    Article  PubMed  CAS  Google Scholar 

  • Ohnishi M, Wada A, Tsutamoto T, Fukai D, Sawaki M, Maeda Y, Kinoshita M (1998) Chronic effects of a novel, orally active endothelin receptor antagonist, T-0201, in dogs with congestive heart failure. J Cardiovasc Pharmacol 31 [Suppl 1]: S236–238

    Article  PubMed  CAS  Google Scholar 

  • Patel T, Galbraith S, McAuley M, Doherty A, Graham D, McCulloch J (1995) Therapeutic potential of endothelin receptor antagonists in experimental stroke. J Cardiovasc Pharmacol 26 [Suppl 3]:S412-S415

    PubMed  CAS  Google Scholar 

  • Patt WC, Edmunds JJ, Repine JT, Berryman KA, Reisdorph BR, Lee C, Plummer, MS, Shahripour A, Haleen SJ, Keiser JA, Flynn MA, Welch KM, Reynolds EE, Rubin R, Tobias B, Hallak H, Doherty AM (1997) Structure-activity relationships in a series of orally active Ƴ-hydroxy butenolide endothelin antagonists. J Med Chem 40:1063–1074

    Article  PubMed  CAS  Google Scholar 

  • Raju B, Okun I, Stavros F, Chan MF (1997a) Search for surrogates: A study of endothelin receptor antagonist structure activity relationships. Bioorg Med Chem Lett 7:933–938

    Article  CAS  Google Scholar 

  • Raju B, Okun I, Stavros F, Chan MF (1997b) Amide bond surrogates: A study in thiophenesulfonamide based endothelin receptor antagonists. Bioorg Med Chem Lett 7:939–944

    Article  CAS  Google Scholar 

  • Raju B, Wu C, Castillo RS, Okun IEJ, Stavros F, Chan MF (1997c) 2-Aryloxycarbonylthiophene-3-sulfonamides: highly potent and ETA selective endothelin receptor antagonists. Bioorg Med Chem Lett 7(16):2093–2098

    Article  CAS  Google Scholar 

  • Raju B, Wu C, Kois A, Verner EJ, Okun I, Stavros F, Chan MF (1996) Thiophenesulfonamides as endothelin antagonists. Bioorg Med Chem Lett 6(22):2651–2656

    Article  CAS  Google Scholar 

  • Riechers H, Albrecht H-P, Amberg W, Baumann E, Bernard H, Bohm H-J, Klinge D, Kling A, Muller S, Raschack M, linger L, Walker N, Wernet W (1996) Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists. J Med Chem 39:2123–2128

    Article  PubMed  CAS  Google Scholar 

  • Roux S, Breu V, Giller T, Neidhart W, Ramuz H, Coassolo P, Clozel JP, Clozel M (1997) Ro 61–1790, a new hydrosoluble endothelin antagonist: general pharmacology and effects on experimental cerebral vasospasm. J Pharmacol Exp Ther 283(3):1110–1118

    PubMed  CAS  Google Scholar 

  • Sakai S, Miyauchi T, Kobayashi T, Yamaguchi I, Goto K, Sugishita Y (1998) Altered expression of isoforms of myosin heavy chain mRNA in the failing rat heart is ameliorated by chronic treatment with an endothelin receptor antagonist. J Cardiovasc Pharmacol 31 [Suppl 1 Endothelin V]:S302-S305

    Article  PubMed  CAS  Google Scholar 

  • Sakaki J, Murata T,Yuumoto Y, Nakamura I, Frueh T, Pitterna T, Iwasaki G, Oda K, Yamamura T, Hayakawa K (1998a) Discovery of IRL 3461: A novel and potent endothelin antagonist with balanced ETA/ETB affinity. Bioorg Med Chem Lett 8:2241–2246

    Article  PubMed  CAS  Google Scholar 

  • Sakaki J, Murata T,Yuumoto Y, Nakamura I, Hayakawa K (1998b) Stereoselective synthesis of a novel and bifunctional endothelin antagonist IRL 3630. Bioorg Med Chem Lett 8:2247–2252

    Article  PubMed  CAS  Google Scholar 

  • Saudek V, Hoflack J, Pelton JT (1989) 1H-NMR study of endothelin, sequence specific assignment of the spectrum and a solution structure. FEBS Lett 257:145–148

    Article  PubMed  CAS  Google Scholar 

  • Spinella MJ, Malik AB, Everitt J, Anderson TT (1991) Design and synthesis of a specific endothelin-1 antagonist: effects on pulmonary vasoconstriction. Proc Natl Acad Sci USA 88:7443–7446

    Article  PubMed  CAS  Google Scholar 

  • Stein PD, Hunt JT, Floyd DM, Moreland S, Dickinson KE Jr, Mitchell C, Liu EC-K, Webb ML, Murugesan N, Dickey J, McMullen D, Zhang R, Lee VG, Serafino R, Delany C, Schaeffer TR, Kozlowski M (1994) The discovery of sulfonamide endothelin antagonists and the development of the orally active ETA antagonist 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-l-naphthalenesulfonamide. J Med Chem 37:329–331

    Article  PubMed  CAS  Google Scholar 

  • Tasker AS, Sorensen BK, Jae H-S, Winn M, Von Geldern TW, Dixon DB, Chiou WJ, Dayton BD, Calzadila S, Hernandes L, Marsh KC, WuWong JR, Opgenorth TJ (1997) Potent and selective non-benzodioxole-containing endothelin-A receptor antagonists. J Med Chem 40:332–340

    Article  Google Scholar 

  • Urade Y, Fujitani Y, Oda K, Watakabe T, Umemura I, Takai M, Okada T, Ssakata K, Karaki H (1992) An endothelin B receptor-selective antagonist: IRL 1038, [Cys11-Cys15]-endothelin-1(11–12). FEBS Lett 311:12–16

    Article  PubMed  CAS  Google Scholar 

  • Von Geldern T (1999) ABT-627 and beyond: An update on Abbott’s endothelin antagonist program. In: Book of Abstracts 217th ACS National Meeting March 21–25 1999. American Chemical Society, Washington, DC, MEDI-136

    Google Scholar 

  • Wakimasu M, Kikuchi T, Kubo K, Asami T, Ohtaki T, Fujino M (1993) Studies on endothelin antagonists. In: Testa B (ed) Perspectives in medical chemistry. Verlag Helvetica Chim Acta Basel, pp 165–177

    Google Scholar 

  • Walsh TF, Fitch KJ, Williams DL Jr, Murphy KL, Nolan NA, Pettibone DJ, Chang RSL, O’Malley SS, Clineschmidt BV, Veber DF, Greenlee WJ (1995) Potent dual antagonists of endothelin and angiotensin II receptors derived from α-phenoxyphenylacetic acids (part III). Bioorg Med Chem Lett 5:1155–1158

    Article  CAS  Google Scholar 

  • Warner TD, Allcock GH, Vane JR (1993) The endothelin receptor antagonist PD 142893 inhibits endothelium-dependent vasodilatations induced by endothelin/ sarafotoxin peptides. Br J Pharmacol 109:56P

    Google Scholar 

  • Williams DL Jr, Murphy KA, Nolan NA, O’Brian DJ, Pettibone DJ, Kivlighn SD, Krause SM, Lis EV Jr, Zingaro GJ, Gabel RA, Clayton FC, Siegl PKS, Zhang K, Naue J, Vyas K, Walsh TF, Fitch KJ, Chakravaty PK, Greenlee WJ, Clineschmidt BV (1995) Pharmacology of L-754142, a highly potent, orally active, nonpeptidyl endothelin antagonist. J Pharmacol Exp Ther 275:1518–1526

    PubMed  CAS  Google Scholar 

  • Winn M, von Geldern TW, Opgenorth TJ, Jae H-S, Tasker AS, Boyd SA, Kester JA, Mantei RA, Bal R, Sorensen BK, Wu-Wong JR, Chiou WJ, Dixon DB, Novosad EI, Hernandez L, Marsh KC (1996) 2,4-Diarylpyrrolidine-3-carboxylic acidspotent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. J Med Chem 39:1039–1048

    Article  PubMed  CAS  Google Scholar 

  • Wu C, Chan MF, Stavros F, Raju B, Okun I, Castillo RS (1997a) Structure-activity relationships of N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboamides as selective endothelin receptor-A antagonists. J Med Chem 40:1682–1689

    Article  PubMed  CAS  Google Scholar 

  • Wu C, Chan MF, Stavros F, Raju B, Okun I, Mong S, Kellerm KM, Brock T, Kogan TP, Dixon RAF (1997b) Discovery of TBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist. J Med Chem 40:1690–1697

    Article  PubMed  CAS  Google Scholar 

  • Wu-Wong JR, Chiou WJ, Naugles KE Jr, Opgenorth TJ (1994) Endothelin receptor antagonists exhibit diminishing potency following incubation with agonist. Life Sci 54:1727–1734

    Article  PubMed  CAS  Google Scholar 

  • Xiang J-N, Luengo JI, Ohlstein EH, Elliott JD (1999) Endothelin receptor antagonists. In: Book of Abstracts, 217th ACS National Meeting March 21–25 1999 American Chemical Society, Washington, DC, MEDI-136

    Google Scholar 

  • Xiang J-N, Atkinson ST, Gao A, Corbett DF, MacPherson DT, Nambi P, Ohlstein EH, Elliott JD (1997) A Novel series of ETA selective antagonists. In: Book of Abstracts, 214th ACS National Meeting. Sept. 7–11 1997. American Chemical Society, Washington, DC MEDI-206

    Google Scholar 

  • Yu M, Gopalakrishnan V, McNeill JR (1998) Hemodynamic effect of a selective endothelin-A receptor antagonist in deoxycorticosterone acetate-salt hypertensive rats. J Cardiovasc Pharmacol 31 [Suppl 1]:S262-S264

    Article  PubMed  CAS  Google Scholar 

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Authors
  1. J. D. Elliott
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  2. J.-N. Xiang
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Editors and Affiliations

  1. Department of Cardiac, Vascular and Inflammation Research, The William Harvey Research Institute St. Barthomew’s and the Royal London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK

    Timothy D. Warner Ph.D

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© 2001 Springer-Verlag Berlin Heidelberg

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Elliott, J.D., Xiang, JN. (2001). Endothelin Receptor Antagonists. In: Warner, T.D. (eds) Endothelin and Its Inhibitors. Handbook of Experimental Pharmacology, vol 152. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-56899-2_9

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  • DOI: https://doi.org/10.1007/978-3-642-56899-2_9

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