過活動膀胱 (Overactive Bladder) 治療薬を指向した選択的β_3アドレナリン受容体(β_3-AR)アゴニストの創製 Discovery of Novel Selective Human β_3 Adrenergic Receptor Agonists as Potential Overactive Bladder (OAB) Therapies

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β-Adrenoceptors (β-ARs) are classified into three types; β<sub>1</sub>-, β<sub>2</sub>-, and β<sub>3</sub>-ARs. In humans, the detrusor muscle has recently been reported to be the predominant site of β<sub>3</sub>-AR mRNA expression. The relaxation induced by adrenergic stimulation of the human detrusor is mediated mainly through β<sub>3</sub>-AR activation, suggesting that β<sub>3</sub>-adrenergic receptor agonists may represent as potential drugs for treating overactive bladder (OAB). In this paper, we described that the synthesis and discovery of novel class of biphenyl analogues containing an carboxylic acid moiety and acylsulfonamide, which has been identified highly potent and selective human β<sub>3</sub>-AR agonists with good oral bioavailability. We also described scalable process for our clinical candidate of FK4664 and AS1714955. Furthermore, in a metabolism study of benzoic acid analogues conducted in human hepatocytes, we identified an acylglucuronide conjugated metabolite (M-2), and the M-2 metabolite of FK4664 was prepared with high selectivity.

収録刊行物

  • 有機合成化学協会誌

    有機合成化学協会誌 69(12), 1402-1410, 2011-12-01

    社団法人 有機合成化学協会

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各種コード

  • NII論文ID(NAID)
    10030480623
  • NII書誌ID(NCID)
    AN0024521X
  • 本文言語コード
    JPN
  • 資料種別
    ART
  • ISSN
    00379980
  • NDL 記事登録ID
    023364696
  • NDL 請求記号
    Z17-256
  • データ提供元
    CJP書誌  NDL  J-STAGE 
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