N-Aryl Isoleucine Derivatives as Angiotensin II AT2 Receptor Ligands

Authors

  • Dr. Malte Behrends,

    1. Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala (Sweden)
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  • Dr. Charlotta Wallinder,

    1. Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala (Sweden)
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  • Dr. Anna Wieckowska,

    1. Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala (Sweden)
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  • Dr. Marie-Odile Guimond,

    1. Service of Endocrinology and Department of Physiology and Biophysics, Faculty of Medicine, University of Sherbrooke, Sherbrooke, QC J1H 5N4 (Canada)
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  • Prof. Anders Hallberg,

    1. Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala (Sweden)
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  • Prof. Nicole Gallo-Payet,

    1. Service of Endocrinology and Department of Physiology and Biophysics, Faculty of Medicine, University of Sherbrooke, Sherbrooke, QC J1H 5N4 (Canada)
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  • Prof. Mats Larhed

    Corresponding author
    1. Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala (Sweden)
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Abstract

A novel series of ligands for the recombinant human AT2 receptor has been synthesized utilizing a fast and efficient palladium-catalyzed procedure for aminocarbonylation as the key reaction. Molybdenum hexacarbonyl [Mo(CO)6] was employed as the carbon monoxide source, and controlled microwave heating was applied. The prepared N-aryl isoleucine derivatives, encompassing a variety of amide groups attached to the aromatic system, exhibit binding affinities at best with Ki values in the low micromolar range versus the recombinant human AT2 receptor. Some of the new nonpeptidic isoleucine derivatives may serve as starting points for further structural optimization. The presented data emphasize the importance of using human receptors in drug discovery programs.

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