Stereoselective Behavior of the Functional Diltiazem Analogue 1-[(4-Chlorophenyl)sulfonyl]-2-(2-thienyl)pyrrolidine, a New L-Type Calcium Channel Blocker
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- 作者：Emanuele Carosati ; Roberta Budriesi ; Pierfranco Ioan ; Gabriele Cruciani ; Fabio Fusi ; Maria Frosini ; Simona Saponara ; Francesco Gasparrini ; Alessia Ciogli ; Claudio Villani ; Philip J. Stephens ; Frank J.
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：November 12, 2009
- 年：2009
- 卷：52
- 期：21
- 页码：6637-6648
- 全文大小：1052K
- 年卷期：v.52,no.21(November 12, 2009)
- ISSN：1520-4804
文摘
We studied the stereoselective behavior of 1-[(4-chlorophenyl)sulfonyl]-2-(2-thienyl)pyrrolidine, a recently described blocker of cardiovascular L-type calcium channels that binds to the diltiazem site. Given the stereocenter at C-2 of the pyrrolidine ring, the two enantiomers were separated by chiral HPLC and, using VCD in conjunction with DFT calculations of chiroptical properties, the absolute configuration was assigned as R-(+)/S-(−). For both forms, functional, electrophysiological, and binding properties were studied and the three-dimensional superimpositions of the two enantiomers over diltiazem were obtained in silico. The significant differences observed for the two enantiomers well agreed with the experimental data, and molecular regions were hypothesized as responsible for the cardiac stereoselectivity and vascular stereospecificity.