Shyamali Ghosh

Nonpeptide Urotensin-II Receptor Antagonists: A New Ligand Class Based on Piperazino-Phthalimide and Piperazino-Isoindolinone Subunits

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.

A concise synthesis of an indenopyrrolidine-based dual αvβ3/αvβ5 integrin antagonist

A new class of dual α v β 3 /α v β 5 integrin antagonists containing a central cis-fused cyclopentane ring was identified. Because of its increased structural rigidity, the indenopyrrolidine ring system provides insight intothe active conformation of other α v β 3 ligands. A concise synthesis of the indenopyrrolidine ring system was accomplished by 1,3-dipolar cycloaddition. Individual isomers of the most active compound were separated by chiral HPLC and their biological activities were compared.