Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor

  • ACS Med Chem Lett. 2013 May 7;4(6):560-4. doi: 10.1021/ml400049p.
Nicolas Dreyfus  1 ,  Jason K Myers  2 ,  Valentina O Badescu  2 ,  Oscar de Frutos  3 ,  Maria Luz de la Puente  3 ,  Chunjin Ding  2 ,  Sandra A Filla  2 ,  Karsten Fynboe  4 ,  Douglas L Gernert  2 ,  Beverly A Heinz  2 ,  Susan K Hemrick-Luecke  2 ,  Kirk W Johnson  2 ,  Michael P Johnson  2 ,  Pilar López  3 ,  Patrick L Love  4 ,  Laura J Martin  2 ,  Thierry Masquelin  2 ,  Michael J McCoy  2 ,  Javier Mendiola  3 ,  Denise Morrow  2 ,  Mark Muhlhauser  2 ,  Gustavo Pascual  3 ,  Thomas J Perun  2 ,  Lance A Pfeifer  2 ,  Lee A Phebus  2 ,  Simon J Richards  1 ,  Juan Antonio Rincón  3 ,  Eric P Seest  2 ,  Jikesh Shah  2 ,  Jia Shaojuan  2 ,  Rosa Maria A Simmons  2 ,  Gregory A Stephenson  2 ,  Eric G Tromiczak  2 ,  Linda K Thompson  2 ,  Magnus W Walter  1 ,  Wayne W Weber  2 ,  Hamideh Zarrinmayeh  2 ,  Craig E Thomas  2 ,  Elizabeth Joshi  2 ,  Smriti Iyengar  2 ,  Anette M Johansson  2
Affiliations
  • 1. Research and Development, Eli Lilly and Company Ltd. , Sunninghill Road, Windlesham, Surrey GU20 6PH, United Kingdom.
  • 2. Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
  • 3. Lilly S.A. , Centro de Investigación, Avda. de la Industria, 30, Alcobendas-Madrid 28108, Spain.
  • 4. Covance, Inc. , Greenfield, Indiana 46140, United States.
PMID: 24900709 DOI: 10.1021/ml400049p
Abstract

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.

Keywords
NET; SERT; SERT RO; SNRI; dual; pain; reuptake inhibitor; α-MMT.