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Modular, efficient synthesis of asymmetrically substituted piperazine scaffolds as potent calcium channel blockers

TitleModular, efficient synthesis of asymmetrically substituted piperazine scaffolds as potent calcium channel blockers
Publication TypeJournal Article
Year of Publication2013
AuthorsBorzenko, A, Pajouhesh, H, Morrison, J-L, Tringham, E, Snutch, TP, Schafer, LL
JournalBioorganic & Medicinal Chemistry Letters
Volume23
Pagination3257-3261
Date PublishedJUN 1
ISSN0960-894X
Abstract

A novel approach to the synthesis of substituted piperazines and their investigation as N-type calcium channel blockers is presented. A common scaffold exhibiting high activity as N-type blockers is N-substituted piperazine. Using recently developed titanium and zirconium catalysts, we describe the efficient and modular synthesis of 2,5-asymmetrically disubstituted piperazines from simple amines and alkynes. The method requires only three isolation/purification protocols and no protection/deprotection steps for the diastereoselective synthesis of 2,5-dialkylated piperazines in moderate to high yield. Screening of the synthesized piperazines for N-type channel blocking activity and selectivity shows the highest activity for a compound with a benzhydryl group on the nitrogen (position 1) and an unprotected alcohol-functionalized side chain. (C) 2013 Elsevier Ltd. All rights reserved.

DOI10.1016/j.bmcl.2013.03.114