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

Laura Fumagalli, Marco Pallavicini, Roberta Budriesi, Cristiano Bolchi, Mara Canovi, Alberto Chiarini, Giuseppe Chiodini, Marco Gobbi, Paola Laurino, Matteo Micucci, Valentina Straniero, Ermanno Valoti

Research output: Contribution to journalArticlepeer-review

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 α1D1B 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.

Original languageEnglish
Pages (from-to)6402-6412
Number of pages11
JournalJournal of Medicinal Chemistry
Volume56
Issue number16
DOIs
Publication statusPublished - Aug 22 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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