Pyrrolinone-Based Peptidomimetics: “Let the Enzyme or Receptor be the Judge”

Peptides and proteins, evolved by nature to perform vital biological functions, would constitute ideal candidates for therapeutic intervention were it not for their generally poor pharmacokinetic profiles. Nonpeptide peptidomimetics have thus been pursued because they might overcome these limitations while maintaining both the potency and selectivity of the parent peptide or protein. Since the late 1980s, we have sought to design, synthesize, and evaluate a novel, proteolytically stable nonpeptide peptidomimetic scaffold consisting of a repeating structural unit amenable to iterative construction; a primary concern is maintaining both the appropriate peptide-like side-chains and requisite hydrogen bonding. In this Account, we detail how efforts in the Smith−Hirschmann laboratories culminated in the identification of the 3,5-linked polypyrrolinone scaffold.We developed effective synthetic protocols, both in solution and on solid supports, for iterative construction of diverse polypyrrolinones that present ...