Design, synthesis, and SAR of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1

Christopher L Cioffi; Mark A Wolf; Peter R Guzzo; Kashinath Sadalapure; Visweswaran Parthasarathy; Dattatraya Dethe; Jun-Ho Maeng; Edmund Carulli; David T J Loong; Xiao Fang; Min Hu; Priya Gupta; Mark Chung; Mei Bai; Nick Moore; Michele Luche; Yuri Khmelnitsky; Patrick L Love; Megan A Watson; Andrew J Mhyre; Shuang Liu

doi:10.1016/j.bmcl.2013.01.006

Design, synthesis, and SAR of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1

Bioorg Med Chem Lett. 2013 Mar 1;23(5):1257-61. doi: 10.1016/j.bmcl.2013.01.006. Epub 2013 Jan 11.

Affiliation

¹ AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA. christopher.cioffi@amriglobal.com

PMID: 23380375
DOI: 10.1016/j.bmcl.2013.01.006

Abstract

The design, synthesis, and structure-activity relationships (SAR) of a series of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1) are described. Optimization of the benzamide and central ring components of the core scaffold led to the identification of a GlyT-1 inhibitor that demonstrated in vivo activity in a rodent cerebral spinal fluid (CSF) glycine model.

MeSH terms

Animals
Benzamides / chemical synthesis
Benzamides / chemistry*
Benzamides / pharmacology*
Glycine / cerebrospinal fluid
Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
Glycine Plasma Membrane Transport Proteins / metabolism
HEK293 Cells
Humans
Microsomes, Liver / metabolism
Piperazines / chemical synthesis
Piperazines / chemistry
Piperazines / pharmacology
Rats
Structure-Activity Relationship

Substances

Benzamides
Glycine Plasma Membrane Transport Proteins
Piperazines
Glycine