Antagonists of angiotensin AT₁ receptors

Czech version

Authors: Pavol Ježko; Milan Remko
Authors‘ workplace: Univerzita Komenského v Bratislave, Farmaceutická fakulta, Katedra farmaceutickej chémie
Published in: Čes. slov. Farm., 2011; 60, 171-181
Category: Review Articles

Overview

The medicinal agents which block AT₁ receptors are used for the treatment of hypertension, cardiac failure, and renal diseases. In clinical practice they have been available already for 15 years. All antagonists of AT₁ receptors were projected without any knowledge of the space (3D) structure of the AT₁ receptor. At present several strategies of projecting antihypertensive drugs are used, which are based on the influence on a number of receptors (e.g. the endothelial ones), not only angiotensin AT₁ receptors. With the use of rational methods of drug projecting based on the knowledge of the spatial structure of the active site of the AT₁ receptor, a development of new highly effective ligands for the therapy of cardiovascular diseases will be made possible. In the future, a development of drugs can be expected, which will block not only the angiotensin AT₁ receptors, but which will be able to influence also other endogenous ligands, e.g. endothelin and nitric oxide.

Key words:
RAAS – AT₁ receptors – antagonists of AT₁ receptors

Sources

1. Frohlich, E. D.: Renin-angiotensin system inhibition improves coronary flow reserve in hypertension. J. Cardiovasc. Pharmacol. 2001; 37, S35–S39.

2. Opie, L. H., Sack, M. N.: Enhanced angiotensin II activity in heart failure: reevaluation of the counterregulatory hypothesis of receptor subtypes. Circ. Res. 2001; 88, 654–658.

3. Ruster, C., Wolf, G.: Renin-angiotensin-aldosterone system and progression of renal disease. J. Am. Soc. Nephrol. 2006; 17, 2985–2991.

4. Triller, D. M., Evang, S. D., Tadrous, M., Yoo, B. K.: First renin inhibitor, aliskiren, for the treatment of hypertension. Pharm. World. Sci. 2008; 30, 741–749.

5. De Gasparo, M., Alexander, W., Bernstein, K. E., Catt, K. J., Goodfriend, T. L., Horiuchi, M., Husain, A., Inagami, T., Timmermans, P. B., Unger, T.: Angiotensin receptors. Last modified on 2010-12-22. Accessed on 2011-05-02. IUPHAR database (IUPHAR-DB). http://www.iuphar-db.org/DATABASE/FamilyMenu Forward?familyId=6..

6. Guimaraes, S., Carneiro, C., Brandao, F., Pinheiro, H., Albino-Teixeira, A., Moura, D.: A pharmacological differentiation between postjunctional (AT_1A) and prejunctional (AT_1B) angiotensin II receptors in the rabbit aorta. Naunyn Schmiedebergs Arch. Pharmacol. 2004; 370, 262–269.

7. Jones, S. E, Vinh, A., McCarthy, C. A., Gaspari, T. A., Widdop R.E.: AT₂ receptors: Functional relevance in cardiovascular disease. Pharmacol. Ther. 2008; 120, 292–316.

8. Oro, C., Qian, H., Thomas, W. G.: Type 1 angiotensin receptor pharmacology: Signaling beyond G proteins. Pharmacol. Ther. 2007; 113, 210–226.

9. Gether, U.: Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr. Rev. 2000; 21, 90–113.

10. Streeten, D. H. P., Anderson, G. H. Jr., Freiberg, J. M., Freiberg, J. M., Dalakos, T. G. N.: Use of an angiotensin II antagonist (Saralasin) In: The recognition of „angiotensin-ogenic” hypertension. Engl. J. Med. 1975; 292, 657-662.

11. Moore, A. F., Fulton, R. W.: Angiotensin II antagonists-saralasin. Drug Dev. Res. 1984; 4, 331-349.

12. Furukawa, Y., Kishimoto, S., Nishikawa, K.: Hypotensive imidazole derivatives. United States Patent 4340598, 1982.

13. Furukawa, Y., Kishimoto, S., Nishikawa, K.: Hypotensive imidazole-5-acetic acid derivatives. United States Patent 4355040, 1982.

14. Wong, P. C., Chiu, A. T., Price, W. A., Thoolen, M. J., Carini, D. J., Johnson, A. L., Taber, R. I., Timmermans, P. B.: Nonpeptide angiotensin II receptor antagonists. I. Pharmacological characterization of 2-n-butyl-4-chloro-1-(2-chlorobenzyl) imidazole-5-acetic acid, sodium salt (S-8307). J. Pharmacol. Exp. Ther. 1988; 247, 1–7.

15. Chiu, A. T., Carini, D. J., Johnson, A. L., McCall, D. E., Price, W. A., Thoolen, M. J. M. C., Wong, P. C., Taber, R. I., Timmermans, P. B.: Nonpeptide angiotensin II (AII) receptor antagonists II. Pharmacology of S-8308. Eur. J. Pharmacol. 1988; 157, 13–21.

16. Duncia, J. V., Chiu, A. T., Carini, D. J., Gregory, G. B., Johnson, A. L., Price, W. A., Wells, G. J., Wong, P. C., Calabrese, J. C., Timmermans, P. B.: The discovery of potent nonpeptide angiotensin II receptor antagonists: A new class of potent antihypertensives. J. Med. Chem. 1990; 33, 1312–1329.

17. Chiu, A. T., Duncia, J. V., McCall, D. E., Wong, P. C., Price, W.A. Jr., Thoolen, M. J., Carini, D. J., Johnson, A. L., Timmermans, P. B.: Nonpeptide angiotensin II receptor antagonists. III. Structure-function studies. J. Pharmacol. Exp. Ther. 1989; 250, 867–874.

18. Carini, D. J., Duncia, J. V., Aldrich, P. E., Chiu, A. T., Johnson, A. L., Pierce, M. E., Price, W. A., Santella, J. B., Wells, G. J.: Nonpeptide angiotensin II receptor antagonists: the discovery of a series of N-(biphenylylmethyl)imidazoles as potent, orally active antihypertensives. J. Med. Chem. 1991; 34, 2525–2547.

19. Aulakh, G. K., Sodhi, R. K., Singh, M.: An update on non-peptide angiotensin receptor antagonists and related RAAS modulators. Life Sci. 2007; 81, 615–639.

20. Wexler, R. R., Greenlee, W. J., Irvin, J. D., Goldberg, M. R., Prendergast, K., Smith, R. D., Timmermans, P. B.: Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy. J. Med. Chem. 1996; 39, 625–656.

21. Miura, S., Fujino, M., Hanzawa, H., Kiya, Y., Imaizumi, S., Matsuo, Y., Tomita, S., Uehara, Y., Karnik S. S., Yanagisawa, H., Koike, H.,Komuro, I., Saku, K.: Molecular mechanism underlying inverse agonist of angiotensin II type I receptor. J. Biol. Chem. 2006; 281, 19288–19295.

22. Underwood, D. J., Strader, C. D., Rivero, R., Patchett, A. A., Greenlee, W., Prendergast, K.: Structural model of antagonist and agonist binding to the angiotensin II, AT₁ subtype, G protein coupled receptor. Chem. Biol. 1994; 1, 211–221.

23. Verheijen, I., Fierens, F. L. P., De Backer, J. P., Vauquelin, G., Vanderheyden, P.: Interaction between the partially insurmountable antagonist valsartan and human recombinant angiotensin II type 1 receptors. Fundam. Clinic. Pharmacol. 2000; 14, 577–585.

24. Verheijen, I., De Backer, J. P., Vanderheyden, P., Vauquelin, G.: A two-state model of antagonist–AT₁ receptor interaction: further support by binding studies at low temperature. Biochem. Pharmacol. 2003; 65, 1339–1341.

25. Bhuiyan, M. A., Ishiguro, M., Hossain, M., Nakamura, T., Ozaki, M., Miura, S., Nagatomo, T.: Binding sites of valsartan, candesartan and losartan with angiotensin II receptor 1 subtype by molecular modeling. Life Sci. 2009; 85, 136–140.

26. Bondensgaad, K., Ankersen, M., Thogersen, H., Hansen, B. S., Wulff, B. S., Bywater, R. P.: Recognition of Privileged Structures by G-Protein Coupled Receptors. J. Med. Chem. 2004; 47, 888–899.

27. Ohno, K., Amano,Y., Kakuta, H., Niimi, T., Takakura, S., Orita, M., Miyata, K., Sakashita, H., Takeuchi, M., Komuro, I., Higaki, J.,Horiuchi, M., Kim-Mitsuyama, S., Mori, Y., Morishita, R., Yamagishi, S.: Unique “delta lock’’ structure of telmisartan is involved in its strongest binding affinity to angiotensin II type 1 receptor. Biochem. Biophys. Res. Commun. 2010; 404, 434–737.

28. Krovat, E. M., Langer, T.: Non-Peptide Angiotensin II Receptor Antagonists: Chemical Feature Based Pharmacophore Identification. J. Med. Chem. 2003; 46, 716–726.

29. Wong, P. C., Price, W. A. Jr., Chiu, A.T., Duncia, J. V., Carini, D. J., Wexler, R. R., Johnson, A. L., Timmermans, P. B.: An active metabolite of DuP 753, an orally active antihypertensive agent. J. Pharmacol. Exp. Ther. 1990; 255, 211–217.

30. Christ, D. D., Kilkson, T., Wong, N., Lam, G. N.: Formation and disposition of EXP3174, a pharmacologically active metabolite of the novel angiotensin II receptor antagonist DuP 753. In.: International Society for the study of Xenobiotica. San Diego 1990; 137.

31. Ries, U. J., Mihm, G., Narr, B., Hasselbach, K. M., Wittneben, H., Entzeroth, M., Van Meel, J. C. A., Wienen, W., Hauel, N. H.: 6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: synthesis, biological activity, and structure-activity relationships. J. Med. Chem. 1993; 36, 4040–4051.

32. Stasch, J.-P., Knorr, A., Hirth-Dietrich, C., Kramer, T., Hubsch, W., Dressel, J., Fey, P., Beuck, M., Sander, E., Frobel, K., Kazda, S.: Long-term blockade of the angiotensin II receptor in renin transgenic rats, salt-loaded Dahl rats, and stroke-prone spontaneously hypertensive rats. Arzneimittelforschung/Drug Research. 1997; 47, 1016–1023.

33. Breithaupt-Grogler, K., Malerczyk, C., Belz, G. G., Butzer, R., Herrmann, V., Stass, H., Wensing, G.: Pharmacodynamic and pharmacokinetic properties of an angiotensin II receptor antagonist characterization by use of Schild regression technique in man. Int. J. Clin. Pharmacol. Ther. 1997; 35, 434–441.

34. Knorr, A., Stasch, J. P., Beuck, M., Bisschoff, F., Fröbel, F., Hubch, C., Hirth-Dietrich, S., Kramer, T.: Pharmacology of BAY 10-6734, an AT₁-selective angiotensin II receptor antagonist. Naunyn Schmeidebergs Arch. Pharmacol. 1996; 353, R69.

35. Wang, J. M., Tan, J., Leenen, F. H.: Central nervous system blockade by peripheral administration of AT₁ receptor blockers. J. Cardiovasc. Pharmacol. 2003; 41, 593–599.

36. Tamura, K., Okuhira, M., Amano, H., Inokuma, K.-I., Hirata, T., Mikoshiba, I., Hashimoto, K.: Pharmacological profiles of KRH-594, a novel nonpeptide angiotensin II-receptor antagonist. J. Cardiovasc. Pharmacol. 1997; 30, 607–615.

37. Inada, Y., Murakami, M., Tazawa, S., Akahane, M.: KRH-594, a new angiotensin AT₁ receptor antagonist, ameliorates nephropathy and hyperlipidaemia in diabetic spontaneously hypertensive rats. Clin. Exp. Pharmacol. Physiol. 2000; 27, 270–276.

38. Mochizuki, S., Sato, T., Furata, K., Hase, K., Ohkura, Y., Fukai, C., Kosakai, K., Wakabayashi, A., Tomiyama, A.: Pharmacological properties of KT3-671, a novel nonpeptide angiotensin II receptor antagonist. J. Cardiovasc. Pharmacol. 1995; 25, 22–29.

39. Yanagisawa, T., Ueyama, N., Kawai, T., Sonegawa, M., Baba, H., Mochizuki, S., Kozakai, K., Tomiyama, T.: 4,5,6,7-Tetrahydro-8-oxo-cycloheptimidazoles: a new class of potent nonpeptide angiotensin II receptor antagonist. Bioorg. Med. Chem. Lett. 1993; 3, 1559–1564.

40. Takata, Y., Tajima, S., Mochizuki, S., Suzaka, H., Tomiyama, A., Kato, H.: Antihypertensive activity and pharmacokinetics of KD3-671, a nonpeptide AT₁-receptor antagonist, in renal hypertensive dogs. J. Cardiovasc. Pharmacol. 1998; 32, 834–844.

41. Amano, H., Fujimoto, K., Suzuki, T., Fujii, T., Mochizuki, S., Tomiyama, A., Kawashima, K.: Antihypertensive effect of chronic KT3-671, a structurally new nonpeptide angiotensin AT₁-receptor antagonist in strokeprone spontaneously hypertensive rats. Jpn. J. Pharmacol. 1995; 69, 215–222.

42. Takata, Y., Kurihara, J., Yoda, T., Suzuki, S., Matsuoka, Y., Okubo, Y., Koto, H.: KT3-671, an angiotensin AT₁ receptor antagonist, attenuates vascular but not cardiac responses to sympathetic nerve stimulation in pithed rats. J. Cardiovasc. Pharmacol. 2001; 37, 427–436.

43. Waeber, B.: Achieving blood pressure targets in the management of hypertension. Blood Press. Suppl. 2001; 2, 6–12.

44. Gavras, H. P.: Issues in hypertension: drug tolerability and special populations. Am. J. Hypertens. 2001; 14, 231S–236S.

45. Imai, T., Hirata, Y., Emori, T., Yanagisawa, M., Masaki, T., Marumo, F.: Induction of endothelin-1 gene by angiotensin and vasopressin in endothelial cells. Hypertension. 1992; 19, 753–757.

46. Chua, B. H., Chua, C. C., Diglio, C. A., Siu, B. B.: Regulation of endothelin-1 mRNA by angiotensin II in rat heart endothelial cells. Biochim. Biophys. Acta. 1993; 1178, 201–206.

47. Ikeda, T., Ohta, H., Okada, M., Kawai, N., Nakao, R., Siegl, P. K. S., Kobayashi, T., Miyauchi, T., Nishikibe, M.: Antihypertensive effects of a mixed endothelin-A- and -B-receptor antagonist, J-104132, were augmented in the presence of an AT₁-receptor antagonist, MK-954. J. Cardiovasc. Pharmacol. 2000; 36, S337–S341.

48. Massart, P. E., Hodeige, D. G., Van Mechelen, H., Charlier, A. A., Ketelslegers, J. M., Heyndrickx G. R., Donckier, J.E.: Angiotensin II and endothelin-1 receptor antagonists have cumulative hypotensive effects in canine Page hypertension. J. Hypertens. 1998; 16, 835–841.

49. Murugesan, N., Tellew, J, E,, Gu, Z,, Kunst, B. L., Fadnis, L., Cornelius, L.A., Baska, R. A., Yang, Y., Beyer, S. M., Monshizadegan, H., Dickinson, K. E., Panchal, B., Valentine, M.T., Chong, S., Morrison, R. A., Carlson, K. E., Powell, J.R., Moreland, S., Barrish, J. C., Kowala, M. C., Macor, J. E.: Discovery of N-Isoxazolyl Biphenylsulfonamides as Potent Dual Angiotensin II and Endothelin A Receptor Antagonists. J. Med. Chem. 2002; 45, 3829–3835.

50. Murugesan, N., Gu, Z., Fadnis, L., Tellew, J. E., Baska, R. A., Yang, Y., Beyer, S. M., Monshizadegan, H., Dickinson, K.E., Valentine, M.T., Humphreys, W.G., Lan, S. J., Ewing, W. R., Carlson, K. E., Kowala, M. C., Zahler, R., Macor, J. E.: Dual Angiotensin II and Endothelin A Receptor Antagonists: Synthesis of 2’-Substituted N-3-Isoxazolyl Biphenylsulfonamides with Improved Potency and Pharmacokinetics. J. Med. Chem. 2005; 48, 171–179.

51. Loscalzo, J., Welch G.: Nitric oxide and its role in the cardiovascular system. Prog. Cardiovasc. Dis. 1995; 38, 87–104.

52. Giles, T. D.: Aspects of nitric oxide in health and disease: a focus on hypertension and cardiovascular disease. J. Clin. Hypertens. (Greenwich). 2006; 8, 2–16.

53. Martelli, A., Breschi, M. C., Calderone, V.: Pharmacodynamic hybrids coupling established cardiovascular mechanisms of action with additional nitric oxide releasing properties. Curr. Pharm. Des. 2009; 15, 614–636.

54. Breschi, M. C., Calderone, V., Digiacomo, M., Macchia, M., Martelli, A., Martinotti, E., Minutolo, F., Rapposelli, S., Rossello, A., Testai, L., Balsamo, A.: New NO-Releasing Pharmacodynamic Hybrids of Losartan and Its Active Metabolite: –Design, Synthesis, and Biopharmacological Properties. J. Med. Chem. 2006; 49, 2628–2639.

55. Breschi, M. C., Calderone, V., Digiacomo, M., Martelli, A., Martinotti, E., Minutolo, F., Rapposelli, S., Balsamo, A.: NO-Sartans: A New Class of Pharmacodynamic Hybrids as Cardiovascular Drugs. J. Med. Chem. 2004; 47, 5597–5600.

56. Li, Y. Q., Ji, H., Zhang, Y. H., Shi, W. B., Meng, Z. K., Chen, X. Y., Du, G. T., Tian, J.: WB1106, a novel nitric oxide-releasing derivative of telmisartan, inhibits hypertension and improves glucose metabolism in rats. Eur. J. Pharmacol. 2007; 577, 100–108.

57. Kurtz, T. W., Klein, U.: Next generation multifunctional angiotensin receptor blockers. Hypertension Res. 2009; 32, 826–834.

58. Baleanu-Gogonea, C., Karnik, S.: Model of the whole rat AT₁ receptor and the ligand-binding site. J. Mol. Model. 2006; 12, 325–337.

59. Liefde, I. V., Vauquelin, G.: Sartan-AT₁ receptor interactions: in vitro evidence for insurmountable antagonism and inverse agonism. Mol. Cell Endocrinol. 2009; 302, 237–243.