Discovery of a Potent, Dual Serotonin and Norepinephrine Reuptake Inhibitor

• Published in: ACS medicinal chemistry letters 2013-06, Vol.4 (6), p.560-564
• Main Authors: Dreyfus, Nicolas, Myers, Jason K, Badescu, Valentina O, de Frutos, Oscar, de la Puente, Maria Luz, Ding, Chunjin, Filla, Sandra A, Fynboe, Karsten, Gernert, Douglas L, Heinz, Beverly A, Hemrick-Luecke, Susan K, Johnson, Kirk W, Johnson, Michael P, López, Pilar, Love, Patrick L, Martin, Laura J, Masquelin, Thierry, McCoy, Michael J, Mendiola, Javier, Morrow, Denise, Muhlhauser, Mark, Pascual, Gustavo, Perun, Thomas J, Pfeifer, Lance A, Phebus, Lee A, Richards, Simon J, Rincón, Juan Antonio, Seest, Eric P, Shah, Jikesh, Shaojuan, Jia, Simmons, Rosa Maria A, Stephenson, Gregory A, Tromiczak, Eric G, Thompson, Linda K, Walter, Magnus W, Weber, Wayne W, Zarrinmayeh, Hamideh, Thomas, Craig E, Joshi, Elizabeth, Iyengar, Smriti, Johansson, Anette M
• Format: Article
• Language: English
• Subjects: Letter
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml400049p

The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug–drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.