944255-95-2Relevant articles and documents
Nonpeptide urotensin-II receptor antagonists: A new ligand class based on piperazino-phthalimide and piperazino-isoindolinone subunits
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.
experimental part, p. 7432 - 7445 (2010/06/19)
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-flushmodel. Adiscussion 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.
