2. Academic Validation
  3. Nonpeptide urotensin-II receptor antagonists: a new ligand class based on piperazino-phthalimide and piperazino-isoindolinone subunits

Nonpeptide urotensin-II receptor antagonists: a new ligand class based on piperazino-phthalimide and piperazino-isoindolinone subunits

  • J Med Chem. 2009 Dec 10;52(23):7432-45. doi: 10.1021/jm900683d.
Edward C Lawson 1,  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,  Bruce E Maryanoff
Affiliations

Affiliation

  • 1 Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, Pennsylvania 19477-0776, USA.
PMID: 19731961 DOI: 10.1021/jm900683d
Abstract

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.

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