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Dual Angiotensin II and Endothelin A Receptor Antagonists:  Synthesis of 2‘-Substituted N-3-Isoxazolyl Biphenylsulfonamides with Improved Potency and Pharmacokinetics

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    Dual Angiotensin II and Endothelin A Receptor Antagonists:  Synthesis of 2‘-Substituted N-3-Isoxazolyl Biphenylsulfonamides with Improved Potency and Pharmacokinetics
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    Discovery Chemistry and Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2005, 48, 1, 171–179
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    https://doi.org/10.1021/jm049548x
    Published December 15, 2004
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    In a previous report we demonstrated that merging together key structural elements present in an AT1 receptor antagonist (1, irbesartan) with key structural elements in a biphenylsulfonamide ETA receptor antagonist (2) followed by additional optimization provided compound 3 (Figure 1) as a dual-action receptor antagonist (DARA), which potently blocked both AT1 and ETA receptors. Described herein are our efforts directed toward improving both the pharmacokinetic profile as well as the AT1 and ETA receptor potency of 3. Our efforts centered on modifying the 2‘-side chain of 3 and examining the isoxazolylsulfonamide moiety in 3. This effort resulted in the discovery of 7 (Figure 1) as a highly potent second-generation DARA. Compound 7 also showed substantially improved pharmacokinetic properties compared to 3. In rats, DARA 7 reduced blood pressure elevations caused by intravenous infusion of Ang II or big ET-1 to a greater extent and with longer duration than DARA 3 or AT1 or ETA receptor antagonists alone. Compound 7 clearly demonstrated superiority over irbesartan (an AT1 receptor antagonist) in the normal SHR model of hypertension in a dose-dependent manner, demonstrating the synergy of AT1 and ETA receptor blockade in a single molecule.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2005, 48, 1, 171–179
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    https://doi.org/10.1021/jm049548x
    Published December 15, 2004
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