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Chemical Compound Review

LS-172913     8-ethyl-3,5-dimethyl-9-[4-[2- (2H-tetrazol...

Synonyms: PDSP1_000578, PDSP2_000576, AC1L3XF7, L-158,809, C23H21N7, ...
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Disease relevance of L-158809


High impact information on L-158809

  • METHODS AND RESULTS: In separate studies, three Ang II receptor antagonists, including AT1 selective (L-158,809), balanced AT1/AT2 (L-163,082), and AT2 selective (L-164,282) agents, were evaluated for their ability to inhibit vascular intimal thickening in a porcine coronary artery model of vascular injury [6].
  • Preliminary studies in a rat carotid artery model revealed that constant infusion of L-158,809 (0.3 or 1.0 mg X kg-1 X d-1) reduced the neointimal cross-sectional area by up to 37% measured 14 days after balloon dilatation [6].
  • The agonistic effect of L-162,313 was blocked by the AT1-specific antagonist L-158,809 and was not observed in untransfected cells [7].
  • PD 123319 completely inhibited 125I-AII binding, with an IC50 of 30 nM, whereas L-158,809 (1 microM) had no significant effect on 125I-AII binding [8].
  • METHODS: We measured renal sympathetic nerve activity (RSNA) in response to graded hypoxia before and after intravenous administration of Ang II (20 ng/kg/min, i.v. 30 min) or AT1 receptor antagonist (L-158,809, 0.33 mg/kg, i.v.) in conscious sham and pacing-induced CHF rabbits [3].

Chemical compound and disease context of L-158809


Biological context of L-158809


Anatomical context of L-158809

  • L-158,809 treatment in podocytes inhibited the increase in p27(Kip1) mRNA expression by 84%, and protein expression by 89% (P < 0.05). p27(Kip1) mRNA and protein expression in diabetic + ARB glomeruli were also significantly reduced by 78% and 85%, respectively, compared with diabetic glomeruli (P < 0.01) [18].
  • DESIGN AND METHODS: Microdialysis probes were placed in the left ventricular (LV) myocardium of eight anaesthetized pigs, three of which were untreated and five treated with the angiotensin II type 1 (AT1) receptor antagonist L-158,809 (10 mg intracoronary) [19].
  • The AII blocker study had a similar design, except that the nephropathy was the result of total body irradiation and bone marrow transplantation and the treatments were no treatment or continuous treatment with an AII blocker, L-158,809 (20 mg/l in drinking water) [20].
  • Phagocytosis was evaluated by incubating microspheres containing the angiotensin II antagonist, L-158,809, with the macrophages in the presence or absence of the phagocytosis inhibitor cythochalasin D [21].
  • The arterial media cross-sectional area and media to lumen ratio were reduced by L-158,809 treatment (0.6 mg/kg dose) [22].

Associations of L-158809 with other chemical compounds


Gene context of L-158809

  • Cells were stimulated with Ang II and the effect was modulated by Ang II type 1 (AT1) and AT2 receptor blockers DUP753 or L-158809 and PD-123319, respectively [27].
  • 2. In the absence of NO blockade, the AT1-R antagonist L-158809 (500 nM) antagonized the Ang II-induced vasoconstrictions, while the AT2-R antagonist PD-123319 (500 nM) had no effect [15].
  • L-158,809 (5,7-dimethyl-2-ethyl-3-[[2'-(1H-tetrazol-5yl)[1,1']-bi- phenyl-4-yl]-methyl]-3H-imidazo[4,5-b]pyridine) is a potent, competitive and specific antagonist of AT1 subtype of angiotensin II (AII) receptors in in vitro radioligand binding and functional isolated tissue assays [28].
  • L-158,809 demonstrated a very high selectivity for the AT1 compared to the AT2 receptor subtype (AT2 IC50 greater than or equal to 10 microM) [23].
  • L-158,809 was antihypertensive in high renin hypertensive rats (aortic coarction) and volume-depleted rhesus monkeys [28].

Analytical, diagnostic and therapeutic context of L-158809

  • Neither L-158,809, L-163,082, nor L-164,282 had statistically significant effects (P=.12, P=.75, and P=.48, respectively, compared with vehicle-treated controls) on neointimal thickness (normalized for degree of injury) measured by morphometric analysis at day 28 after angioplasty [6].
  • Furthermore, the alterations of LV diastolic properties in the LVH group could not be attributed to myocardial perfusion, which was rather decreased by administration of enalaprilat and L-158,809 [9].
  • The plasma concentrations of L-158,809 varied considerably between monkeys after oral administration [24].
  • RESULTS: The average yield of L-158,809 microspheres (10% (w/w)) was 95% of the theoretical loading [29].
  • VEGF mRNA was also significantly higher in diabetic kidneys than in the control groups, with a significant reduction in VEGF mRNA in L-158,809-treated diabetic kidneys [30].


  1. Blocking angiotensin II synthesis/activity preserves glomerular nephrin in rats with severe nephrosis. Benigni, A., Tomasoni, S., Gagliardini, E., Zoja, C., Grunkemeyer, J.A., Kalluri, R., Remuzzi, G. J. Am. Soc. Nephrol. (2001) [Pubmed]
  2. AT1 receptor antagonist treatment caused persistent arterial functional changes in young spontaneously hypertensive rats. Gillies, L.K., Lu, M., Wang, H., Lee, R.M. Hypertension (1997) [Pubmed]
  3. Angiotensin II enhances carotid body chemoreflex control of sympathetic outflow in chronic heart failure rabbits. Li, Y.L., Xia, X.H., Zheng, H., Gao, L., Li, Y.F., Liu, D., Patel, K.P., Wang, W., Schultz, H.D. Cardiovasc. Res. (2006) [Pubmed]
  4. Temporal regression of myocyte hypertrophy in hypertensive, heart failure-prone rats treated with an AT1-receptor antagonist. Tamura, T., Said, S., Andersen, S.M., McCune, S.A., Mochizuki, S., Gerdes, A.M. J. Card. Fail. (2002) [Pubmed]
  5. Effect of the novel angiotensin II type 1 receptor antagonist L-158,809 on acute infarct expansion and acute anterior myocardial infarction in the dog. Ford, W.R., Khan, M.I., Jugdutt, B.I. The Canadian journal of cardiology. (1998) [Pubmed]
  6. Effects of subtype-selective and balanced angiotensin II receptor antagonists in a porcine coronary artery model of vascular restenosis. Huckle, W.R., Drag, M.D., Acker, W.R., Powers, M., McFall, R.C., Holder, D.J., Fujita, T., Stabilito, I.I., Kim, D., Ondeyka, D.L., Mantlo, N.B., Chang, R.S., Reilly, C.F., Schwartz, R.S., Greenlee, W.J., Johnson, R.G. Circulation (1996) [Pubmed]
  7. Non-peptide angiotensin agonist. Functional and molecular interaction with the AT1 receptor. Perlman, S., Schambye, H.T., Rivero, R.A., Greenlee, W.J., Hjorth, S.A., Schwartz, T.W. J. Biol. Chem. (1995) [Pubmed]
  8. Photoaffinity labeling of subtype 2 angiotensin receptor of human myometrium. Servant, G., Boulay, G., Bossé, R., Escher, E., Guillemette, G. Mol. Pharmacol. (1993) [Pubmed]
  9. Diastolic properties in canine hypertensive left ventricular hypertrophy: effects of angiotensin converting enzyme inhibition and angiotensin II type-1 receptor blockade. Hayashida, W., Donckier, J., Van Mechelen, H., Charlier, A.A., Pouleur, H. Cardiovasc. Res. (1997) [Pubmed]
  10. Angiotensin II receptor antagonist, L-158,809, prevents intimal hyperplasia in dog grafted veins. Yuda, A., Takai, S., Jin, D., Sawada, Y., Nishimoto, M., Matsuyama, N., Asada, K., Kondo, K., Sasaki, S., Miyazaki, M. Life Sci. (2000) [Pubmed]
  11. Renoprotective mechanisms of angiotensin II antagonism in experimental chronic renal failure. Uhlenius, N., Miettinen, A., Vuolteenaho, O., Tikkanen, I. Kidney Blood Press. Res. (2002) [Pubmed]
  12. Inducible nitric oxide synthase (iNOS) expression is increased in lipopolysaccharide (LPS)-stimulated diabetic rat glomeruli: effect of ACE inhibitor and angiotensin II receptor blocker. Lee, H.Y., Noh, H.J., Gang, J.G., Xu, Z.G., Jeong, H.J., Kang, S.W., Choi, K.H., Han, D.S. Yonsei Med. J. (2002) [Pubmed]
  13. Cross-over study comparing effects of treatment with an angiotensin converting enzyme inhibitor and an angiotensin II type 1 receptor antagonist on cardiovascular changes in hypertension. Gillies, L.K., Werstiuk, E.S., Lee, R.M. J. Hypertens. (1998) [Pubmed]
  14. Combined effects of angiotensin converting enzyme inhibition and angiotensin II receptor antagonism in conscious pigs with congestive heart failure. Shen, Y.T., Wiedmann, R.T., Greenland, B.D., Lynch, J.J., Grossman, W. Cardiovasc. Res. (1998) [Pubmed]
  15. AT2-antagonist sensitive potentiation of angiotensin II-induced vasoconstrictions by blockade of nitric oxide synthesis in rat renal vasculature. Muller, C., Endlich, K., Barthelmebs, M., Helwig, J.J. Br. J. Pharmacol. (1997) [Pubmed]
  16. Differential regulation of prostaglandin synthesis by angiotensin peptides in porcine aortic smooth muscle cells: subtypes of angiotensin receptors involved. Jaiswal, N., Tallant, E.A., Jaiswal, R.K., Diz, D.I., Ferrario, C.M. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
  17. Bleomycin-induced apoptosis of alveolar epithelial cells requires angiotensin synthesis de novo. Li, X., Zhang, H., Soledad-Conrad, V., Zhuang, J., Uhal, B.D. Am. J. Physiol. Lung Cell Mol. Physiol. (2003) [Pubmed]
  18. Angiotensin II receptor blocker inhibits p27Kip1 expression in glucose-stimulated podocytes and in diabetic glomeruli. Xu, Z.G., Yoo, T.H., Ryu, D.R., Cheon Park, H., Ha, S.K., Han, D.S., Adler, S.G., Natarajan, R., Kang, S.W. Kidney Int. (2005) [Pubmed]
  19. Cardiac interstitial fluid levels of angiotensin I and II in the pig. Schuijt, M.P., van Kats, J.P., de Zeeuw, S., Duncker, D.J., Verdouw, P.D., Schalekamp, M.A., Danser, A.H. J. Hypertens. (1999) [Pubmed]
  20. Radiation nephropathy is treatable with an angiotensin converting enzyme inhibitor or an angiotensin II type-1 (AT1) receptor antagonist. Moulder, J.E., Fish, B.L., Cohen, E.P. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. (1998) [Pubmed]
  21. Influence of surface properties at biodegradable microsphere surfaces: effects on plasma protein adsorption and phagocytosis. Lacasse, F.X., Filion, M.C., Phillips, N.C., Escher, E., McMullen, J.N., Hildgen, P. Pharm. Res. (1998) [Pubmed]
  22. Effects of chronic blockade of angiotensin II receptor on the maintenance of hypertension and vascular changes in spontaneously hypertensive rats. Gillies, L.K., Lee, R.M. Can. J. Physiol. Pharmacol. (1996) [Pubmed]
  23. In vitro pharmacology of L-158,809, a new highly potent and selective angiotensin II receptor antagonist. Chang, R.S., Siegl, P.K., Clineschmidt, B.V., Mantlo, N.B., Chakravarty, P.K., Greenlee, W.J., Patchett, A.A., Lotti, V.J. J. Pharmacol. Exp. Ther. (1992) [Pubmed]
  24. Disposition of the angiotensin II receptor antagonist L-158,809 in rats and rhesus monkeys. Colletti, A.E., Krieter, P.A. Drug Metab. Dispos. (1994) [Pubmed]
  25. Angiotensin II binding sites on micro-organisms contaminating cell cultures. Whitebread, S., Pfeilschifter, J., Ramjoué, H., de Gasparo, M. Regul. Pept. (1993) [Pubmed]
  26. Angiotensin II receptor antagonists in the prevention of radiation nephropathy. Moulder, J.E., Fish, B.L., Cohen, E.P., Bonsib, S.M. Radiat. Res. (1996) [Pubmed]
  27. Angiotensin II regulates 11beta-hydroxysteroid dehydrogenase type 2 via AT2 receptors. Lanz, B., Kadereit, B., Ernst, S., Shojaati, K., Causevic, M., Frey, B.M., Frey, F.J., Mohaupt, M.G. Kidney Int. (2003) [Pubmed]
  28. In vivo pharmacology of L-158,809, a new highly potent and selective nonpeptide angiotensin II receptor antagonist. Siegl, P.K., Chang, R.S., Mantlo, N.B., Chakravarty, P.K., Ondeyka, D.L., Greenlee, W.J., Patchett, A.A., Sweet, C.S., Lotti, V.J. J. Pharmacol. Exp. Ther. (1992) [Pubmed]
  29. Improved activity of a new angiotensin receptor antagonist by an injectable spray-dried polymer microsphere preparation. Lacasse, F.X., Hildgen, P., Pérodin, J., Escher, E., Phillips, N.C., McMullen, J.N. Pharm. Res. (1997) [Pubmed]
  30. Angiotensin II receptor blocker attenuates overexpression of vascular endothelial growth factor in diabetic podocytes. Lee, E.Y., Shim, M.S., Kim, M.J., Hong, S.Y., Shin, Y.G., Chung, C.H. Exp. Mol. Med. (2004) [Pubmed]
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