Stereochemical Requirements for the Mineralocorticoid Receptor Antagonist Activity of Dihydropyridines
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- 作者：Graciela B. Arhancet ; Scott S. Woodard ; Jessica D. Dietz ; Danny J. Garland ; Grace M. Wagner ; Kaliappan Iyanar ; Joe T. Collins ; James R. Blinn ; Randal E. Numann ; Xiao Hu ; Horng-Chih Huang
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：May 27, 2010
- 年：2010
- 卷：53
- 期：10
- 页码：4300-4304
- 全文大小：761K
- 年卷期：v.53,no.10(May 27, 2010)
- ISSN：1520-4804
文摘
A number of known 1,4-dihydropyridine CCBs were identified as having comparable potency to the steroidal MR antagonist eplerenone. Chiral resolution of mebudipine revealed that MR and CCB activity reside in opposite enantiomers. Small molecule X-ray crystal structures showed that the C4 stereochemistry of optimized selective MR analogues, e.g. 5, is consistent with MR-active mebudipine. Molecular modeling supports a binding pose consistent with that previously proposed for DHP diesters.