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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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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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