Synthesis and Biological Evaluation of N-((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter-1
File(s)Synthesis and biological evaluation Cioffi.pdf (2.18 MB)
Accepted version
Author(s)
Type
Journal Article
Abstract
We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship (SAR) exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic (PK) and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid (CSF) glycine biomarker model in both rodents and non-human primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).
Date Issued
2016-08-25
Date Acceptance
2016-06-17
Citation
Journal of Medicinal Chemistry, 2016, 59 (18), pp.8473-8494
ISSN
0022-2623
Publisher
American Chemical Society
Start Page
8473
End Page
8494
Journal / Book Title
Journal of Medicinal Chemistry
Volume
59
Issue
18
Copyright Statement
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, © 2016 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acs.jmedchem.6b00914.
Subjects
Medicinal & Biomolecular Chemistry
0304 Medicinal And Biomolecular Chemistry
1115 Pharmacology And Pharmaceutical Sciences
0305 Organic Chemistry
Publication Status
Published