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Design, synthesis, and docking studies of telmisartan analogs for the treatment of metabolic syndrome

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Abstract

In our early studies, telmisartan was found to be a moderate peroxisome proliferator-activated receptor (PPAR) gamma activator in the human PPARγ-GAL-4 cell-based transactivation assay. Thus, novel analogs of telmisartan were designed, synthesized, and evaluated in the AT1 receptor binding assay and PPAR gamma transactivation assay. A total of 11 compounds were designed based on docking in both AT1 receptor model and PPAR gamma active pocket and synthesized. Introduction of an additional acidic group at the para position of the distal phenyl ring of telmisartan decreased affinity towards AT1 receptor and PPARγ activity. In the present study, the molecule with best results was MT003 with weak PPARγ activity (8% of maximum PPARγ activation achieved by full agonist rosiglitazone at 10 μM) and good binding affinity (K i = 650 ± 139 nM) towards the AT1 receptor. Docking of MT003 into AT1 receptor model and PPAR gamma showed very similar interactions with the receptors as AT1 antagonist telmisartan and PPAR gamma agonist rosiglitazone.

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Acknowledgments

We would like to acknowledge NIH Grant 2R42AR44767-02A2 (Bethesda Pharmaceuticals) for supporting this project.

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Authors and Affiliations

  1. Department of Medicinal Chemistry and Laboratory for Applied Drug Design and Synthesis, School of Pharmacy, University of Mississippi, 417 Faser Hall, University, MS, 38677, USA

    Cassia S. Mizuno, Akshay Patny & Mitchell A. Avery

  2. Department of Medicinal Chemistry and Laboratory for Applied Drug Design and Synthesis, School of Pharmacy, University of Mississippi, 431 Faser Hall, University, MS, 38677, USA

    Amar G. Chittiboyina

  3. Department of Laboratory Medicine, University of California, San Francisco, CA, 94122, USA

    Theodore W. Kurtz

  4. Department of Family Medicine, University of California, Irvine, CA, 92668, USA

    Harrihar A. Pershadsingh

  5. Bethesda Pharmaceuticals, Inc., 404 Windsor Park Drive, Bakersfield, CA, 93311, USA

    Harrihar A. Pershadsingh

  6. Department of Pharmacology, School of Pharmacy, University of Mississippi, University, MS, 38677, USA

    Robert C. Speth & Vardan T. Karamyan

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  1. Cassia S. Mizuno
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  2. Amar G. Chittiboyina
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  3. Akshay Patny
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  5. Harrihar A. Pershadsingh
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  6. Robert C. Speth
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  7. Vardan T. Karamyan
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  8. Mitchell A. Avery
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Correspondence to Mitchell A. Avery.

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Mizuno, C.S., Chittiboyina, A.G., Patny, A. et al. Design, synthesis, and docking studies of telmisartan analogs for the treatment of metabolic syndrome. Med Chem Res 18, 611–628 (2009). https://doi.org/10.1007/s00044-008-9153-9

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  • DOI: https://doi.org/10.1007/s00044-008-9153-9

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