title: Modular, efficient synthesis of asymmetrically substituted piperazine scaffolds as potent calcium channel blockers.
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.
authors: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, Canada V6T 1Z1.
authors: Andrey
authors: A
authors: Borzenko
authors: Hassan
authors: H
authors: Pajouhesh
authors: Jerrie-Lynn
authors: JL
authors: Morrison
authors: Elizabeth
authors: E
authors: Tringham
authors: Terrance P
authors: TP
authors: Snutch
authors: Laurel L
authors: LL
authors: Schafer
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002384:Catalysis; D002460:Cell Line; D006801:Humans; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014025:Titanium / Q000737:chemistry; D015040:Zirconium / Q000737:chemistry
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D010879:Piperazines; D000077489:Piperazine; D015040:Zirconium; D014025:Titanium