Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 1: development of a potent and CNS penetrant [3.1.0]-based lead

Carrie K Jones; Douglas J Sheffler; Richard Williams; Sataya B Jadhav; Andrew S Felts; Ryan D Morrison; Colleen M Niswender; J Scott Daniels; P Jeffrey Conn; Craig W Lindsley

doi:10.1016/j.bmcl.2014.01.013

Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 1: development of a potent and CNS penetrant [3.1.0]-based lead

Bioorg Med Chem Lett. 2014 Feb 15;24(4):1067-70. doi: 10.1016/j.bmcl.2014.01.013. Epub 2014 Jan 13.

Affiliations

¹ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
² Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
³ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
⁴ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.

Abstract

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach that provided a robust intellectual property position, in lieu of a traditional, expensive HTS campaign. Members within this new [3.1.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, CNS penetration and efficacy in a preclinical model of schizophrenia (prepulse inhibition).

Keywords: GlyT1; Scaffold hopping; Schizophrenia; Transporter.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Bridged Bicyclo Compounds / chemical synthesis
Bridged Bicyclo Compounds / chemistry
Bridged Bicyclo Compounds / pharmacology*
Dose-Response Relationship, Drug
Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
Humans
Molecular Structure
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Structure-Activity Relationship

Substances

Bridged Bicyclo Compounds
Glycine Plasma Membrane Transport Proteins
Piperidines
SLC6A9 protein, human
piperidine

Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 1: development of a potent and CNS penetrant [3.1.0]-based lead

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding