6-Methoxy-7-benzofuranoxy and 6-Methoxy-7-indolyloxy Analogues of 2-[2-(2,6-Dimethoxyphenoxy)ethyl]aminomethyl-1,4-benzodioxane (WB4101):1 Discovery of a Potent and Selective 伪1D-Adrenocept

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• 作者：Laura Fumagalli ; Marco Pallavicini ; Roberta Budriesi ; Cristiano Bolchi ; Mara Canovi ; Alberto Chiarini ; Giuseppe Chiodini ; Marco Gobbi ; Paola Laurino ; Matteo Micucci ; Valentina Straniero ; Ermanno Valoti
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 22, 2013
• 年：2013
• 卷：56
• 期：16
• 页码：6402-6412
• 全文大小：426K
• 年卷期：v.56,no.16(August 22, 2013)
• ISSN：1520-4804

文摘

Previous results have shown that replacement of one of the two o-methoxy groups at the phenoxy residue of the potent, but not subtype-selective, 伪₁-AR antagonist (S)-WB4101 [(S)-1] by phenyl, or by ortho,meta-fused cyclohexane, or especially by ortho,meta-fused benzene preferentially elicits 伪_1D-AR antagonist affinity. Such observations inspired the design of four new analogues of 1 bearing, in lieu of the 2,6-dimethoxyphenoxy residue, a 6-methoxy-substituted 7-benzofuranoxy or 7-indolyloxy group or, alternatively, their corresponding 2,3-dihydro form. Of these new compounds, which maintain, rigidified, the characteristic ortho heterodisubstituted phenoxy substructure of 1, the S enantiomer of the dihydrobenzofuranoxy derivative exhibited the highest 伪_1D-AR antagonist affinity (pA₂ 9.58) with significant 伪_1D/伪_1A and 伪_1D/伪_1B selectivity. In addition, compared both to 伪_1D-AR antagonists structurally related to 1 and to the well-known 伪_1D-AR antagonist BMY7378, this derivative had modest 5-HT_1A affinity and neutral 伪₁-AR antagonist behavior.