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J Med Chem. 2013 Aug 22;56(16):6402-12. doi: 10.1021/jm400867d. Epub 2013 Jul 31.

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.

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  • 1Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Italy.

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.

PMID:
23902232
[PubMed - indexed for MEDLINE]
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