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Chemical Compound Review

CHEMBL438194     (3S)-3-[[(2S)-2-[[(2R)-2- acetamido-3-(4...

Synonyms: CHEBI:240374, PD-142893, AC1L3U2Y, PD 142893, 143037-36-9, ...
 
 
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Disease relevance of PD-142893

 

High impact information on PD-142893

  • PD 142893, a nonselective ETA/ETB antagonist totally blunted this effect [2].
  • A nonselective ETA-ETB receptor antagonist (PD 142893) blocked [3H]thymidine uptake, but ETB receptor-selective agonists (S6c and [Ala1,Ala3,Ala11,Ala15]ET-1(6-21)) were unable to increase [Ca2+]i or [3H]thymidine uptake [3].
  • The nonselective ETA/ETB receptor antagonist PD 142893 blocked both ET and S6c-induced enhancement of the PTH responses [4].
  • We further demonstrated that BQ 123 and PD 142893/PD 145065 inhibited ET-1-stimulated [3H]thymidine uptake but at higher concentrations than required for inhibition of [Ca2+]i increases [5].
  • Inhibition of NO synthesis alone uncovered insulin-induced vasoconstriction at physiological concentrations (21+/-5% from baseline diameter at 34 microU/ml), which was abolished by PD-142893 [6].
 

Biological context of PD-142893

  • Herein, we will describe the structure-activity relationships of Ac-DDip16-Leu-Asp-Ile-Ile-Trp21 (PD 142893) with a particular emphasis on modifications that lead to enhanced receptor affinity and/or individual receptor subtype selectivity [7].
  • Among them, two well-characterized non-selective ETA/ETB antagonists were PD 142893 and PD 145065; interest in these potent ET antagonists was, however, reduced by their peptidic structure which was likely to lead to undesirable properties such as poor bioavailability and short duration of action [8].
 

Anatomical context of PD-142893

 

Associations of PD-142893 with other chemical compounds

  • L-arginine release was transiently increased up to 25-fold on reperfusion (vehicle); release was reduced by SNAP (mean: 68%) and entirely prevented by PD 142893 [13].
  • Bosentan is more efficacious than PD 142893 in inhibiting the venous effects of ET-1 [14].
  • The purpose of this study was to determine whether vascular endothelial and vascular smooth-muscle endothelin ET(B) receptors could be quantitatively differentiated by PD 142893 (PD), SB 209670 (SB), and BQ 788 (BQ) in the same species by using closely matched experimental conditions [15].
  • Bradykinin (0.5 and 1.0 microM) and endothelin-1 (0.01 and 0.1 nM) produced a dose-related increase in the number of venular leaky sites and superfusion of PD 142893 (ETAB antagonist), and PD 147953 and BQ-123 (ETA antagonists) significantly decreased bradykinin- and endothelin-induced responses [16].
  • This paper also describes the development of a pharmacophoric model able to explain the ET receptor binding properties of our hexapeptide analogs compared with those of PD 142893 and PD 145065 and IRL2500, recently reported as a potent ETB selective endothelin antagonist [8].
 

Gene context of PD-142893

  • SB 217242 was 4-, 62- and 125-fold more potent as an ETA receptor antagonist than the previously reported compounds BQ-123, PD 142893 and Ro 46-2005, respectively [17].
  • The mean angiogenic areas in animals with ET-1 antibody, PD 142893, or BQ 123 in the angiogenic mixture were 57.20 +/- 7.5 (P =.06), 46.00 +/- 11.5 (P = 1.0), 8.60 +/- 2.9 (P <.001), respectively [18].
  • These effects suggest mediation by ETB receptors but PD 142893 (10(-5) M) did give a 3 fold antagonism of constrictions induced by SX6c [10].
  • These receptors had similar affinities for a number of ETBR agonists (ET-1, ET-3, S6C, BQ 3020) and antagonists (Ro 47-0203, PD 142893) [19].
  • Inhibition of PI3-kinase, an intracellular mediator of insulin-induced NO production, with wortmannin, also uncovered insulin-induced vasoconstriction (13+/-3% from baseline at 34 microU/ml) that was abolished by PD-142893 [6].

References

  1. Endothelin-1 does not contribute to ischemia/reperfusion-induced vasoconstriction in skeletal muscle. Wang, W.Z., Anderson, G., Acland, R.D., Barker, J. Journal of reconstructive microsurgery. (1997) [Pubmed]
  2. Growth inhibitory properties of endothelin-1 in human hepatic myofibroblastic Ito cells. An endothelin B receptor-mediated pathway. Mallat, A., Fouassier, L., Préaux, A.M., Gal, C.S., Raufaste, D., Rosenbaum, J., Dhumeaux, D., Jouneaux, C., Mavier, P., Lotersztajn, S. J. Clin. Invest. (1995) [Pubmed]
  3. Protein kinase C and protein tyrosine kinase activity contribute to mitogenic signaling by endothelin-1. Cross-talk between G protein-coupled receptors and pp60c-src. Simonson, M.S., Herman, W.H. J. Biol. Chem. (1993) [Pubmed]
  4. EndothelinB receptor activation enhances parathyroid hormone-induced calcium signals in UMR-106 cells. Lee, S.K., Stern, P.H. J. Bone Miner. Res. (1995) [Pubmed]
  5. Characterization of endothelin receptors in mesangial cells: evidence for two functionally distinct endothelin binding sites. Simonson, M.S., Rooney, A. Mol. Pharmacol. (1994) [Pubmed]
  6. Physiological concentrations of insulin induce endothelin-mediated vasoconstriction during inhibition of NOS or PI3-kinase in skeletal muscle arterioles. Eringa, E.C., Stehouwer, C.D., Merlijn, T., Westerhof, N., Sipkema, P. Cardiovasc. Res. (2002) [Pubmed]
  7. Structure-activity relationships of the potent combined endothelin-A/endothelin-B receptor antagonist Ac-DDip16-Leu-Asp-Ile-Ile-Trp21: development of endothelin-B receptor selective antagonists. Cody, W.L., He, J.X., DePue, P.L., Waite, L.A., Leonard, D.M., Sefler, A.M., Kaltenbronn, J.S., Haleen, S.J., Walker, D.M., Flynn, M.A. J. Med. Chem. (1995) [Pubmed]
  8. Toward the rational development of peptidomimetic analogs of the C-terminal endothelin hexapeptide: development of a theoretical model. Macchia, M., Barontini, S., Ceccarelli, F., Galoppini, C., Giusti, L., Hamdan, M., Lucacchini, A., Martinelli, A., Menchini, E., Mazzoni, M.R., Revoltella, R.P., Romagnoli, F., Rovero, P. Farmaco (1998) [Pubmed]
  9. Role of matrix metalloproteinase-2 in thrombin-induced vasorelaxation of rat mesenteric arteries. Fernandez-Patron, C., Radomski, M.W., Davidge, S.T. Am. J. Physiol. Heart Circ. Physiol. (2000) [Pubmed]
  10. Use of the endothelin antagonists BQ-123 and PD 142893 to reveal three endothelin receptors mediating smooth muscle contraction and the release of EDRF. Warner, T.D., Allcock, G.H., Corder, R., Vane, J.R. Br. J. Pharmacol. (1993) [Pubmed]
  11. Comparative studies with the endothelin receptor antagonists BQ-123 and PD 142893 indicate at least three endothelin receptors. Warner, T.D., Allcock, G.H., Mickley, E.J., Corder, R., Vane, J.R. J. Cardiovasc. Pharmacol. (1993) [Pubmed]
  12. Characterization of the potent combined endothelin(A/B)-antagonist PD 142893 on cerebral vessels. Zimmermann, M., Vatter, H., Weyrauch, E., Lange, B.N., Krishnan, R., Raabe, A., Seifert, V. Neurol. Res. (2004) [Pubmed]
  13. Role of endothelin, nitric oxide and L-arginine release in ischaemia/reperfusion injury of rat heart. Brunner, F., Leonhard, B., Kukovetz, W.R., Mayer, B. Cardiovasc. Res. (1997) [Pubmed]
  14. Subtypes of endothelin receptors that mediate venous effects of endothelin-1 in anaesthetized rats. Palacios, B., Lim, S.L., Pang, C.C. Br. J. Pharmacol. (1997) [Pubmed]
  15. PD 142893, SB 209670, and BQ 788 selectively antagonize vascular endothelial versus vascular smooth muscle ET(B)-receptor activity in the rat. Schroeder, R.L., Keiser, J.A., Cheng, X.M., Haleen, S.J. J. Cardiovasc. Pharmacol. (1998) [Pubmed]
  16. Effects of endothelin receptor antagonists on bradykinin-induced increases in macromolecular efflux. Mayhan, W.G., Rubinstein, I. Inflammation (1994) [Pubmed]
  17. Nonpeptide endothelin receptor antagonists. VI: Pharmacological characterization of SB 217242, a potent and highly bioavailable endothelin receptor antagonist. Ohlstein, E.H., Nambi, P., Lago, A., Hay, D.W., Beck, G., Fong, K.L., Eddy, E.P., Smith, P., Ellens, H., Elliott, J.D. J. Pharmacol. Exp. Ther. (1996) [Pubmed]
  18. Amelioration of cyclosporin A effect on microvasculature by endothelin inhibitor. Wilasrusmee, C., Ondocin, P., Bruch, D., Shah, G., Kittur, S., Wilasrusmee, S., Kittur, D.S. Surgery (2003) [Pubmed]
  19. Pharmacological differences between rat and human endothelin B receptors. Reynolds, E.E., Hwang, O., Flynn, M.A., Welch, K.M., Cody, W.L., Steinbaugh, B., He, J.X., Chung, F.Z., Doherty, A.M. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
 
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