Synthesis and in Vitro and in Vivo Characterization of Highly 尾1-Selective 尾-Adrenoceptor Partial Agonists

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• 作者：Shailesh N. Mistry ; Jillian G Baker ; Peter M Fischer ; Stephen J Hill ; Sheila M Gardiner ; Barrie Kellam
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 23, 2013
• 年：2013
• 卷：56
• 期：10
• 页码：3852-3865
• 全文大小：531K
• 年卷期：v.56,no.10(May 23, 2013)
• ISSN：1520-4804

文摘

尾-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human 尾-adrenoceptor subtype involved in these diseases, yet few truly 尾₁-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),JavaScript:void(0);" class="ref">(1) a selective 尾₁-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1鈥檚 aromatic nitrile afforded 19, a ligand with similar 尾₁-adrenoceptor selectivity and partial agonism (log K_D of 鈭?.75 and 鈭?.15 as an antagonist of functional 尾₁- and 尾₂-mediated responses, respectively, and 34% of the maximal response of isoprenaline (尾₁)). In vitro 尾-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and 尾₁-selectivity.