1. Academic Validation
  2. Design and Synthesis of Novel and Selective Glycine Transporter-1 (GlyT1) Inhibitors with Memory Enhancing Properties

Design and Synthesis of Novel and Selective Glycine Transporter-1 (GlyT1) Inhibitors with Memory Enhancing Properties

  • J Med Chem. 2018 Jul 26;61(14):6018-6033. doi: 10.1021/acs.jmedchem.8b00372.
Vincent J Santora 1 Theresa A Almos 1 Richard Barido 1 Jillian Basinger 1 Chris L Bellows 1 Brett C Bookser 1 J Guy Breitenbucher 1 Nicola J Broadbent 1 Clifford Cabebe 1 Chih-Kun Chai 1 Mi Chen 1 Stephine Chow 1 De Michael Chung 1 Lindsay Crickard 1 Anne M Danks 1 Graeme C Freestone 1 Dany Gitnick 1 Varsha Gupta 1 Christine Hoffmaster 1 Andrew R Hudson 1 Alan P Kaplan 1 Michael R Kennedy 1 Dong Lee 1 James Limberis 1 Kiev Ly 1 Chi Ching Mak 1 Brittany Masatsugu 1 Andrew C Morse 1 Jim Na 1 David Neul 1 John Nikpur 1 Marco Peters 1 Robert E Petroski 1 Joel Renick 1 Kristen Sebring 1 Samantha Sevidal 1 Ali Tabatabaei 1 Jenny Wen 1 Yingzhuo Yan 1 Zachary W Yoder 1 Douglas Zook 1
Affiliations

Affiliation

  • 1 Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States.
Abstract

We report here the identification and optimization of a novel series of potent GlyT1 inhibitors. A ligand design campaign that utilized known GlyT1 inhibitors as starting points led to the identification of a novel series of pyrrolo[3,4- c]pyrazoles amides (21-50) with good in vitro potency. Subsequent optimization of physicochemical and in vitro ADME properties produced several compounds with promising pharmacokinetic profiles. In vivo inhibition of GlyT1 was demonstrated for select compounds within this series by measuring the elevation of glycine in the cerebrospinal fluid (CSF) of rats after a single oral dose of 10 mg/kg. Ultimately, an optimized lead, compound 46, demonstrated in vivo efficacy in a rat novel object recognition (NOR) assay after oral dosing at 0.1, 1, and 3 mg/kg.

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