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An efficient synthesis of a rationally designed 1,5 disubstituted imidazole AT1 Angiotensin II receptor antagonist: reorientation of imidazole pharmacophore groups in losartan reserves high receptor affinity and confirms docking studies

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Abstract

A new 1,5 disubstituted imidazole AT1 Angiotensin II (AII) receptor antagonist related to losartan with reversion of butyl and hydroxymethyl groups at the 2-, 5-positions of the imidazole ring was synthesized and evaluated for its antagonist activity (V8). In vitro results indicated that the reorientation of butyl and hydroxymethyl groups on the imidazole template of losartan retained high binding affinity to the AT1 receptor concluding that the spacing of the substituents at the 2,5- positions is of primary importance. The docking studies are confirmed by binding assay results which clearly show a comparable binding score of the designed compound V8 with that of the prototype losartan. An efficient, regioselective and cost effective synthesis renders the new compound as an attractive candidate for advanced toxicological evaluation and a drug against hypertension.

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References

  1. Ferrario CM (1990) J Cardiovasc Pharmacol 15:51–55

    Article  CAS  Google Scholar 

  2. Corvol P (1989) Clin Exp Hypertens 2:463–470

    Google Scholar 

  3. Berecek KH, King SJ, Wu JN (1993) CRC Press: Boca Raton, 183–220

  4. Waeber B, Nussberger J, Brunner HR (eds.) (1990) Raven Press: New York, 2209–2232

  5. Lindgren BR, Andersson RG (1989) Med Toxicol Adverse Drug Exp 4:369–380

    CAS  Google Scholar 

  6. Wexler RR, Greenlee WJ, Irvin JD, Goldberg MR, Prendergast K, Smith RD, Timmermans PBMWM (1996) J Med Chem 39:625–655

    Article  CAS  Google Scholar 

  7. De Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T (2000) Pharmacol Rev 52:415–472

    Google Scholar 

  8. Moore G, Smith J, Baylis B, Matsoukas J (1995) Adv Pharmacol 6:91–141

    Article  Google Scholar 

  9. Giannis A, Bubsam F (1997) Adv Drug Res 29:1–78

    Article  CAS  Google Scholar 

  10. Duncia JV, Carini DJ, Chiu AT, Pierce ME, Price WA, Smith RD, Wells GJ, Wong PC, Wexler RR, Johnson AL, Timmermans PBMWM (1992) Drugs Future 17:326–331

    Google Scholar 

  11. Ashton WT (1994) Exp Opin Invest Drugs 3:1105–1142

    CAS  Google Scholar 

  12. Buhlmayer P (1992) Curr Opin Ther Pat 2:1693–1718

    Google Scholar 

  13. Bradbury RH, Allot CP, Dennis M, Fisher E, Major JS, Masek BB, Oldham AA, Russell ST (1992) J Med Chem 35:4027–4038

    Article  CAS  Google Scholar 

  14. Masek BB, Merchant A, Matthew JB (1993) J Med Chem 36:1230–1238

    Article  CAS  Google Scholar 

  15. Easthope SE, Jarvis B (2002) Drugs 62:1253–1287

    Article  CAS  Google Scholar 

  16. Rabbat CG (2002) ACP J Club 136:82–84

    Google Scholar 

  17. Cheng-Lai A (2002) Heart Dis 4:54–59

    Article  CAS  Google Scholar 

  18. Maillard MP, Rossat J, Brunner HR, Burnier MJ (2000) Pharmacol Exp Ther 295:649–654

    CAS  Google Scholar 

  19. Brunner HR, Gavras H (2002) Lancet 359:990–992

    Article  Google Scholar 

  20. Ismail MAH, Barker S, Abou el-Ella DA, Abouzid KAM, Toubar RA, Todd MH (2006) J Med Chem 49:1526–1535

    Article  CAS  Google Scholar 

  21. Cappelli A, Nannicini C, Gallelli A, Giuliani G, Valenti S, Mohr GP, Anzini M, Mennuni L, Ferrari F, Caselli G, Girdani A, Peris W, Makovec F, Giorgi G, Vomero S (2008) J Med Chem 51:2137–2146

    Article  CAS  Google Scholar 

  22. Theodoropoulou E, Mavromoustakos T, Panagiotopoulos D, Matsoukas JM, Smith J (1996) Lett Pept Sci 3:209–215

    Article  CAS  Google Scholar 

  23. Polevaya L, Mavromoustakos T, Zoumpoulakis P, Crdadolnik S, Roumelioti P, Giatas N, Mutule I, Vlahakos D, Iliodromitis E, Kremastinos D, Matsoukas J (2001) Bioorg Med Chem 9:1639–1647

    Article  CAS  Google Scholar 

  24. Moore GJ, Ganter RC, Matsoukas JM, Hondrelis J, Agelis G, Barlos K, Wilkinson S, Sandall J, Fowler P (1994) J Mol Rec 7:251–256

    Article  CAS  Google Scholar 

  25. Turner RJ, Matsoukas JM, Moore GJ (1991) Biochim Biophys Acta 1065:21–28

    Article  CAS  Google Scholar 

  26. Matsoukas JM, Agelis G, Hondrelis J, Yamdagni R, Wu Q, Ganter R, Smith J, Moore D, Moore GJ (1993) J Med Chem 36:904–911

    Article  CAS  Google Scholar 

  27. Matsoukas JM, Yamdagni R, Moore GJ (1990) Peptides 11:367–374

    Article  CAS  Google Scholar 

  28. Mavromoustakos T, Kolocouris A, Zervou M, Roumelioti P, Matsoukas J, Weisemann R (1999) J Med Chem 42:1714–1722

    Article  CAS  Google Scholar 

  29. Zoumpoulakis P, Politi A, Grdadolnik SG, Matsoukas J, Mavromoustakos T (2006) J Pharm Biomed Anal 40:1097–1104

    Article  CAS  Google Scholar 

  30. Wahhab A, Smith JR, Ganter RC, Moore DM, Hondrelis J, Matsoukas J, Moore GJ (1993) Arzn.-Forsch./Drug Res 43:1157–1168

    CAS  Google Scholar 

  31. Tuccinardi T, Calderone V, Rapposelli S, Martinelli A (2006) J Med Chem 49:4305–4316

    Article  CAS  Google Scholar 

  32. Okada T, Sugihara M, Bondar AN, Elstner M, Entel P, Buss V (2004) J Mol Biol 342:571–583

    Article  CAS  Google Scholar 

  33. Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) J Mol Biol 267:727–748

    Article  CAS  Google Scholar 

  34. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) J Med Chem 49:6177–6196

    Article  CAS  Google Scholar 

  35. Sherman W, Day T, Jacobson MP, Friesner RA, Farid R (2006) J Med Chem 49:534–553

    Article  CAS  Google Scholar 

  36. Schrodinger, LLC: Portland, OR, 2007, Web address: www.schrodinger.com

  37. Jones G, Willett P, Glen RC (1995) J Mol Biol 245:43–53

    Article  CAS  Google Scholar 

  38. Judson S, Jaeger EP, Treasurywala AM (1994) J Mol Struct 308:191–206

    Google Scholar 

  39. Oshiro CM, Kuntz ID, Dixon JS (1995) J Comput -Aided Mol Des 9:113–130

    Article  CAS  Google Scholar 

  40. GOLD user manual, web address: www.ccdc.cam.ac.uk

  41. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) J Comput Chem 30:2785–2791

    Article  CAS  Google Scholar 

  42. Meyers AI, Mihelich ED (1975) J Am Chem Soc 97:7383–7385

    Article  CAS  Google Scholar 

  43. Dordor IM, Mellor JM (1983) Tetrahedron Lett 24:1437–1440

    Article  CAS  Google Scholar 

  44. Duncia JV, Pierce ME, Santella JB (1991) J Org Chem 56:2395

    Article  CAS  Google Scholar 

  45. Noskov SY (2008) Proteins 73(4):851–863

    Article  CAS  Google Scholar 

  46. Barlos K, Papaioannou D, Theodoropoulos D (1982) J Org Chem 47:1324–1326

    Article  CAS  Google Scholar 

  47. Athanasopoulos C, Balayiannis G, Karigiannis G, Papaioannou DA (1999) IOS Press 22:137–151

    Google Scholar 

  48. Athanassopoulos P, Barlos K, Gatos D, Hatzi O, Tzavara C (1995) Tetrahedron Lett 36:5645–5648

    CAS  Google Scholar 

  49. Barlos K, Gatos D (1999) Biopolymers 51:266–278

    Article  CAS  Google Scholar 

  50. Krambovitis E, Hatzidakis G, Barlos K (1998) J Biol Chem 273:10874–10879

    Article  CAS  Google Scholar 

  51. Lauth-de Viguerie N, Sergueeva N, Damiot M, Mawlawi H, Riviere M, Lattes A (1994) Heterocycles 37:1561–1578

    Article  Google Scholar 

  52. Matsoukas JM, Hondrelis J, Keramida M, Mavromoustakos T, Makriyannis A, Yamdagni R, Wu Q, Moore J (1994) J Biol Chem 269:5303–5312

    CAS  Google Scholar 

  53. Matsoukas JM, Agelis G, Wahhab A, Hondrelis J, Panagiotopoulos D, Yamdagni R, Wu Q, Mavromoustakos T, Maia HLS, Ganter R, Moore GJ (1995) J Med Chem 38:4660–4669

    Article  CAS  Google Scholar 

  54. Matsoukas JM, Cordopatis P, Belte U, Goghari MH, Ganter RC, Franklin KJ, Moore GJ (1998) J Med Chem 31:1418–1421

    Article  Google Scholar 

  55. Matsoukas JM, Goghari MA, Scanlon MN, Franklin KJ, Moore GJ (1985) J Med Chem 28:780–783

    Article  CAS  Google Scholar 

  56. Matsoukas J, Hondrelis J, Agelis G, Barlos K, Gatos D, Ganter R, Moore D, Moore G (1994) J Med Chem 37:2958–2969

    Article  CAS  Google Scholar 

  57. Polevaya L, Mavromoustakos T, Zoumboulakis P, Grdadolnik SG, Roumelioti P, Giatas N, Mutule I, Keivish T, Vlahakos DV, Iliodromitis EK, Kremastinos DT, Matsoukas J (2001) Bioorg Med Chem 6:1639–1647

    Article  Google Scholar 

  58. Vlahakos DV, Matsoukas JM, Ancans J, Moore GJ, Iliodromitis EK, Marathias KP, Kremastinos D (1996) Lett Pept Sci 3:191–194

    Article  CAS  Google Scholar 

  59. Matsoukas J, Ancas J, Mavromoustakos T, Kolocouris A, Roumelioti P, Vlahakos D, Yamdagni R, Wu Q, Moore G (2000) Bioorg Med Chem 8:1–10

    Article  CAS  Google Scholar 

  60. Roumelioti P, Polevaya L, Mavromoustakos T, Zoumboulakis P, Giatas N, Mutule I, Keivish T, Zoga A, Vlahakos DV, Iliodromitis EK, Kremastinos DT, Matsoukas J (2002) Bioorg Med Chem 12:2627–2633

    Article  CAS  Google Scholar 

  61. Potamitis C, Zervou M, Katsiaras V, Zoumpoulakis P, Durdagi S, Papadopoulos M, Hayes J, Grdadolnik S, Kyrikou I, Argyropoulos D, Vatougia G, Mavromoustakos T (2009) J Chem Inf Mod 49:726–729

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Ministry of Development of Greece, General Secretariat of Research and Technology, EPET II, 115/PENED, 1999/EPAN, 114 from the Ministry of Education (postgraduate program “Medicinal Chemistry” EPEAEK). We also acknowledge NATO (Linkage Grant 974548). We also acknowledge Prof. J. Findlay and Dr. Alan Cox from School of Biochemistry and Microbiology, University of Leeds, Leeds, LS2 9JT, UK who kindly provided the laboratory facilities to Prof. T. Mavromoustakos a recipient of Royal Society scholarship. We also acknowledge A. Suarez for her linguistic amendment of the manuscript.

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Authors and Affiliations

  1. Department of Chemistry, University of Patras, Patras, 26500, Greece

    George Agelis, Panagiota Roumelioti, Amalia Resvani, Maria-Eleni Androutsou, Konstantinos Kelaidonis & John Matsoukas

  2. University of Calgary, Department of Biological Sciences, Institute for Biocomplexity and Informatics, Calgary, Alberta, Canada

    Serdar Durdagi

  3. Department of Chemistry, University of Athens, Athens, Greece

    Thomas Mavromoustakos

  4. Department of Internal Medicine, ‘ATTIKON’ University Hospital, Athens, Greece

    Demetrios Vlahakos

  5. Eldrug S.A., Patras, Greece

    John Matsoukas

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  1. George Agelis
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Correspondence to George Agelis or John Matsoukas.

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Docking Studies: Serdar Durdagi, Thomas Mavromoustakos

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Agelis, G., Roumelioti, P., Resvani, A. et al. An efficient synthesis of a rationally designed 1,5 disubstituted imidazole AT1 Angiotensin II receptor antagonist: reorientation of imidazole pharmacophore groups in losartan reserves high receptor affinity and confirms docking studies. J Comput Aided Mol Des 24, 749–758 (2010). https://doi.org/10.1007/s10822-010-9371-3

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