2. Academic Validation
  3. Optimization of the choline transporter (CHT) inhibitor ML352: Development of VU6001221, an improved in vivo tool compound

Optimization of the choline transporter (CHT) inhibitor ML352: Development of VU6001221, an improved in vivo tool compound

  • Bioorg Med Chem Lett. 2016 Oct 1;26(19):4637-4640. doi: 10.1016/j.bmcl.2016.08.062.
Jeanette L Bertron 1,  Elizabeth A Ennis 2,  Christopher J Tarr 1,  Jane Wright 1,  Jonathan W Dickerson 2,  Charles W Locuson 1,  Anna L Blobaum 3,  Jerri M Rook 3,  Randy D Blakely 4,  Craig W Lindsley 5
Affiliations

Affiliations

  • 1 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 2 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 3 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 4 FAU Brain Institute, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL 33458, USA. Electronic address: rblakely@fau.edu.
  • 5 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
PMID: 27575469 DOI: 10.1016/j.bmcl.2016.08.062
Abstract

This Letter describes the further lead optimization of the CHT inhibitor probe, ML352 (VU0476201), and the development of VU6001221, an improved in vivo tool. A multi-dimensional optimization effort encountered steep SAR, and ultimately, subtle tuning of the electronics of the central phenyl core provided VU6001221, a CHT inhibitor with comparable potency for choline uptake inhibition as ML352, yet improved PK and CNS penetration. Moreover, VU6001221 enabled evaluation, for the first time, of a CHT inhibitor in a standard preclinical rodent cognition model, novel object recognition (NOR). We observed VU6001221 to elicit a dose-responsive increase in NOR, raising the possibility of agonism of synaptic α7 nicotinic ACh receptors by elevated extracellular choline, that if confirmed would represent a novel molecular strategy to enhance cognition.

Keywords

Choline transporter (CHT); Cognition; ML352; Novel object recognition (NOR); Structure–Activity Relationship (SAR).

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