|Title||Modular, efficient synthesis of asymmetrically substituted piperazine scaffolds as potent calcium channel blockers|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Borzenko, A, Pajouhesh, H, Morrison, J-L, Tringham, E, Snutch, TP, Schafer, LL|
|Journal||Bioorganic & Medicinal Chemistry Letters|
|Date Published||JUN 1|
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.