Nonpeptide Urotensin-II Receptor Antagonists: A New Ligand Class Based on Piperazino-Phthalimide and Piperazino-Isoindolinone Subunits
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- 作者：Edward C. Lawson ; Diane K. Luci ; Shyamali Ghosh ; William A. Kinney ; Charles H. Reynolds ; Jenson Qi ; Charles E. Smith ; Yuanping Wang ; Lisa K. Minor ; Barbara J. Haertlein ; Tom J. Parry ; Bruce P. Damiano
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：December 10, 2009
- 年：2009
- 卷：52
- 期：23
- 页码：7432-7445
- 全文大小：1116K
- 年卷期：v.52,no.23(December 10, 2009)
- ISSN：1520-4804
文摘
We have discovered two related chemical series of nonpeptide urotensin-II (U-II) receptor antagonists based on piperazino-phthalimide (5 and 6) and piperazino-isoindolinone (7) scaffolds. These structure types are distinctive from those of U-II receptor antagonist series reported in the literature. Antagonist 7a exhibited single-digit nanomolar potency in rat and human cell-based functional assays, as well as strong binding to the human U-II receptor. In advanced pharmacological testing, 7a blocked the effects of U-II in vitro in a rat aortic ring assay and in vivo in a rat ear-flush model. A discussion of U-II receptor antagonist pharmacophores is presented, and a specifically defined model is suggested from tricycle 13, which has a high degree of conformational constraint.