Lawson Edward C, Luci Diane K, Ghosh Shyamali, Kinney William A, Reynolds Charles H, Qi Jenson, Smith Charles E, Wang Yuanping, Minor Lisa K, Haertlein Barbara J, Parry Tom J, Damiano Bruce P, Maryanoff Bruce E
Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, Pennsylvania 19477-0776, USA.
J Med Chem. 2009 Dec 10;52(23):7432-45. doi: 10.1021/jm900683d.
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.
我们基于哌嗪基邻苯二甲酰亚胺（5和6）以及哌嗪基异吲哚啉酮（7）骨架发现了两个相关的非肽类尿紧张素II（U-II）受体拮抗剂化学系列。这些结构类型与文献中报道的U-II受体拮抗剂系列不同。拮抗剂7a在基于大鼠和人细胞的功能试验中表现出个位数纳摩尔的效力，并且与人U-II受体有很强的结合力。在高级药理学测试中，7a在体外大鼠主动脉环试验和体内大鼠耳潮红模型中阻断了U-II的作用。本文讨论了U-II受体拮抗剂药效基团，并从具有高度构象限制的三环化合物13提出了一个具体定义的模型。
