Lactams as EP 4 prostanoid receptor subtype selective agonists. Part 1: 2-Pyrrolidinones-stereochemical and lower side-chain optimization

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 7; pp. 1655 - 1659
• Main Authors: Elworthy, Todd R., Kertesz, Denis J., Kim, Woongki, Roepel, Michael G., Quattrocchio-Setti, Lina, Smith, David B., Tracy, Jahari Laurant, Chow, Audrey, Li, Fujun, Brill, Emma R., Lach, Leang K., McGee, Daren, Yang, Diana S., Chiou, San-San
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 2004
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.01.063

A series of 7-[(5 R)-substituted 2-oxo-1-pyrrolidinyl]-heptanoic acids were prepared, their isomeric purity determined, and pharmacologically evaluated. Lactams with affinity for the EP 4 receptor displayed agonist behavior. The lower side-chain of the lactam template could be substituted to afford ligands (e.g., 17, 24, 30, 31, and 33) of high potency and greater than 1000-fold affinity for EP 4 versus the other EP prostanoid receptors. A series of 7-[(5 R)-substituted 2-oxo-1-pyrrolidinyl]-heptanoic acids were prepared, isomeric purity determined, and pharmacologically evaluated. Ligands with affinity at the EP 4 receptor displayed agonist activity as well as high subtype selectivity.