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 α1D Adrenoceptor Antagonist
Articolo
Data di Pubblicazione:
2013
Citazione:
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 α1D Adrenoceptor Antagonist / L. Fumagalli, M. Pallavicini, R. Budriesi, C. Bolchi, M. Canovi, A. Chiarini, G. Chiodini, M. Gobbi, P. Laurino, M. Micucci, V. Straniero, E. Valoti. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 56:16(2013), pp. 6402-6412. [10.1021/jm400867d]
Abstract:
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, α1-AR antagonist (S)-WB4101 [(S)-1] by phenyl, or by ortho,meta-fused cyclohexane, or especially by ortho,meta-fused benzene preferentially elicits α1D-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 α1D-AR antagonist affinity (pA2 9.58) with significant α1D/α1A and α1D/α1B selectivity. In addition, compared both to α1D-AR antagonists structurally related to 1 and to the well-known α1D-AR antagonist BMY7378, this derivative had modest 5-HT1A affinity and neutral α1-AR antagonist behavior.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
L. Fumagalli, M. Pallavicini, R. Budriesi, C. Bolchi, M. Canovi, A. Chiarini, G. Chiodini, M. Gobbi, P. Laurino, M. Micucci, V. Straniero, E. Valoti
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