Synthesis and Biological Evaluation of N-((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter-1

Christopher L. Cioffi, Shuang Liu, Mark A. Wolf, Peter R. Guzzo, Kashinath Sadalapure, Visweswaran Parthasarathy, David T.J. Loong, Jun Ho Maeng, Edmund Carulli, Xiao Fang, Kalesh Karunakaran, Lakshman Matta, Sok Hui Choo, Shailijia Panduga, Ronald N. Buckle, Randall N. Davis, Samuel A. Sakwa, Priya Gupta, Bruce J. Sargent, Nicholas A. MooreMichele M. Luche, Grant J. Carr, Yuri L. Khmelnitsky, Jiffry Ismail, Mark Chung, Mei Bai, Wei Yee Leong, Nidhi Sachdev, Srividya Swaminathan, Andrew J. Mhyre

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

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 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 and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).

Original languageEnglish
Pages (from-to)8473-8494
Number of pages22
JournalJournal of Medicinal Chemistry
Volume59
Issue number18
Early online date9 Sep 2016
DOIs
Publication statusPublished - 22 Sep 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016 American Chemical Society.

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