Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human 尾3-Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side Effects

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• 作者：Yasuhiro Wada ; Hiromitsu Shirahashi ; Taisuke Iwanami ; Masami Ogawa ; Seiji Nakano ; Akifumi Morimoto ; Ken-ichi Kasahara ; Eiichi Tanaka ; Yoshio Takada ; Shigeki Ohashi ; Mutsuhiro Mori ; Satoshi Shuto
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：58
• 期：15
• 页码：6048-6057
• 全文大小：417K
• ISSN：1520-4804

文摘

Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human 尾₃-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant 尾₃-AR agonistic activity (EC₅₀ = 21 nM), it also exhibited agonistic activity at the 伪_1A-AR (EC₅₀ = 219 nM, selectivity: 伪_1A/尾₃ = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for 尾₃-AR agonistic activity versus 伪_1A-AR agonistic activity. Thus, modification of the 3-substituent of the indazole moiety effectively improved the selectivity to develop compound 11 with potent 尾₃-AR agonistic activity (EC₅₀ = 13 nM) and high selectivity (伪_1A/尾₃ = >769-fold). Compound 11 was also inactive toward 尾₁ and 尾₂-ARs and showed dose dependent 尾₃-AR mediated relaxation of marmoset urinary bladder smooth muscle, while it did not obviously affect heart rate or blood pressure (iv, 3 mg/kg) in anesthetized rats.