Efficient synthesis of mibefradil analogues: an insight into <i>in vitro</i> stability

다국어 초록 (Multilingual Abstract)

<P>This article describes the synthesis and biological evaluation of a chemical library of mibefradil analogues to investigate the effect of structural modification on <I>in vitro</I> stability. The construction of the dihydrobenzopyran structure in mibefradil derivatives <B>2</B> was achieved through two efficient approaches based on a diastereoselective intermolecular Reformatsky reaction and an intramolecular carbonyl–ene cyclization. In particular, the second strategy through the intramolecular carbonyl–ene reaction led to the formation of a key intermediate <B>3</B> in a short and highly stereoselective way, which has allowed for practical and convenient preparation of analogues <B>2</B>. Using this protocol, we could obtain 22 new mibefradil analogues <B>2</B>, which were biologically tested for <I>in vitro</I> efficacies against T-type calcium channels and metabolic stabilities. Among the synthesized compounds, we found that analogue <B>2aa</B> containing a dihydrobenzopyran ring and a secondary amine linker showed high % remaining activities of the tested CYP enzymes retaining the excellent T-type calcium channel blocking activity. These findings indicated that the structural modification of <B>1</B> was effective for improving <I>in vitro</I> stability, <I>i.e.</I>, reducing CYP inhibition and metabolic degradation.</P>

<P>Graphic Abstract</P><P>New mibefradil analogues were synthesized by a diastereoselective intramolecular carbonyl–ene reaction as a key transformation. The structural modification of mibefradil significantly reduced CYP inhibition and microsomal degradation.
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