Endothelin receptor antagonist

An endothelin receptor antagonist (ERA) is a drug that blocks endothelin receptors.

Three main kinds of ERAs exist:

CPU0213 also c.f. CPU 86017

• Dual ET Receptor Antagonists, which affect both endothelin A (ET_A) and B receptors (ET_B) ^[2] CPU0213 [821780-32-9] is an example of a dual receptor endothelin receptor antagonist. ^[3]
  • aprocitentan, bosentan, macitentan, tezosentan, Feloprentan (LU-302872 the HCl salt is called LU-420627) [204267-33-4], ^{[4] [5]}
• Selective ET_A Receptor Antagonists, which affect endothelin A receptors
  • sitaxentan, ambrisentan, atrasentan, BQ-123, sparsentan, zibotentan, avosentan, edonentan, clazosentan, Fandosentan ^{[6] [7]}
• Selective ET_B Receptor Antagonists, which affect endothelin B receptors
  • BQ-788 and A192621 are used in research but have not yet reached clinical trial stage

Macitentan, ambrisentan and bosentan are mainly used for the treatment of pulmonary arterial hypertension, while atrasentan is an experimental anti-cancer drug.

Further (unsorted) examples include: BMS-182874, ^[8] BMS-193884, ^[9] BQ-485 [141594-26-5] ^[10] CI 1020 (PD 156707) [162256-50-0] ^{[11] [12]} Enrasentan [167256-08-8], ^[13] J 104132 [198279-45-7], ^[14] L-754142 [173450-67-4], ^[15] PABSA [188710-94-3], ^[16] PD-155080, ^[17] SB 209670 [157659-79-5], ^[18] ZD1611 [186497-38-1] ^[19]

References

1. 刘立刚, 李瑞文, 吉民 & 华维一, CN1445218 (2003).
2. Endothelin receptor antagonists
3. Wang ZY, Zhang W, Li XZ, Han Y, Chen YP, Liu Z, et al. (November 2011). "CPU0213, a novel endothelin type A and type B receptor antagonist, protects against myocardial ischemia/reperfusion injury in rats". Brazilian Journal of Medical and Biological Research. 44 (11): 1148–55. doi: 10.1590/s0100-879x2011007500119 . PMID   21915473.
4. Amberg W, Hergenröder S, Hillen H, Jansen R, Kettschau G, Kling A, et al. (1999). "Discovery and Synthesis of ( S )-3-[2-(3,4-Dimethoxyphenyl)ethoxy]-2- (4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic Acid (LU 302872), a Novel Orally Active Mixed ET_A/ET_B Receptor Antagonist". Journal of Medicinal Chemistry. 42 (16): 3026–3032. doi:10.1021/jm9910425. PMID   10447946.
5. Wilhelm Amberg, et al. WO1998009953 (Abbott GmbH and Co KG).
6. Jacks TE, Belmont DT, Briggs CA, Horne NM, Kanter GD, Karrick GL, et al. (March 2004). "Development of a scalable process for CI-1034, an endothelin antagonist". Organic Process Research & Development. 8 (2): 201–212. doi:10.1021/op034104g.
7. Amy Mae Bunker, et al. U.S. patent 6,545,150 (2003 to Warner Lambert Co LLC).
8. Stein PD, Hunt JT, Floyd DM, Moreland S, Dickinson KE, Mitchell C, et al. (February 1994). "The discovery of sulfonamide endothelin antagonists and the development of the orally active ETA antagonist 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulf onamide". Journal of Medicinal Chemistry. 37 (3): 329–331. doi:10.1021/jm00029a001. PMID   8308857.
9. Murugesan N, Gu Z, Stein PD, Spergel S, Mathur A, Leith L, et al. (August 2000). "Biphenylsulfonamide endothelin receptor antagonists. 2. Discovery of 4'-oxazolyl biphenylsulfonamides as a new class of potent, highly selective ET(A) antagonists". Journal of Medicinal Chemistry. 43 (16): 3111–3117. doi:10.1021/jm000105c. PMID   10956219.
10. US 5696116,Clozel JP, assigned to F Hoffmann La Roche AG 
11. Doherty AM, Patt WC, Edmunds JJ, Berryman KA, Reisdorph BR, Plummer MS, et al. (April 1995). "Discovery of a novel series of orally active non-peptide endothelin-A (ETA) receptor-selective antagonists". Journal of Medicinal Chemistry. 38 (8): 1259–1263. doi:10.1021/jm00008a002. PMID   7731010.
12. Patt WC, Cheng XM, Repine JT, Lee C, Reisdorph BR, Massa MA, et al. (June 1999). "Butenolide endothelin antagonists with improved aqueous solubility". Journal of Medicinal Chemistry. 42 (12): 2162–2168. doi:10.1021/jm980504w. PMID   10377221.
13. US 6288247,Andemichael YW, assigned to SmithKline Beecham Corp 
14. US 6022972,Devine PN, assigned to Merck and Co Inc 
15. WO 1994021590,Bagley SW, assigned to Merck and Co Inc 
16. Iwasaki T, Hayasaki-Kajiwara Y, Matsuo Y, Nakajima M (2001). "Endothelin receptor antagonist activity of (R)-(-)-2-(benzo[1,3]dioxol-5-yl)-N-(4-isopropylphenylsulfonyl)-2-(6-methyl- 2-propylpyridin-3-yloxy)acetamide hydrochloride (PABSA) in rat aortic smooth muscle cells and isolated rat thoracic aorta". Arzneimittel-Forschung. 51 (7): 529–534. doi:10.1055/s-0031-1300076. PMID   11505783.
17. WO 1995005376,Berryman KA, assigned to Warner Lambert Co LLC 
18. US 6448260,Cousins RD, assigned to SmithKline Beecham Corp 
19. WO 1996040681,Bradbury RH, assigned to AstraZeneca UK Ltd, Syngenta Ltd