Optimisation of a series of potent, selective and orally bioavailable GlyT1 inhibitors

Joanne L Thomson; Wesley P Blackaby; Andrew S R Jennings; Simon C Goodacre; Andrew Pike; Steve Thomas; Terry A Brown; Alison Smith; Gopalan Pillai; Leslie J Street; Richard T Lewis

doi:10.1016/j.bmcl.2009.02.102

Optimisation of a series of potent, selective and orally bioavailable GlyT1 inhibitors

Bioorg Med Chem Lett. 2009 Apr 15;19(8):2235-9. doi: 10.1016/j.bmcl.2009.02.102. Epub 2009 Feb 28.

Authors

Joanne L Thomson¹, Wesley P Blackaby, Andrew S R Jennings, Simon C Goodacre, Andrew Pike, Steve Thomas, Terry A Brown, Alison Smith, Gopalan Pillai, Leslie J Street, Richard T Lewis

Affiliation

¹ Department of Medicinal Chemistry, Merck Sharp and Dohme, Neuroscience Research Centre, Harlow, Essex, UK.

PMID: 19318248
DOI: 10.1016/j.bmcl.2009.02.102

Abstract

A series of heterocyclic sulfonamides have been developed which are potent and selective inhibitors of hGlyT1. SAR studies to optimise the in vitro and in vivo properties are described. Optimisation of the central scaffold resulted in cyclohexane sulfones 28 and 29, which have good PK properties and show promise for further development.

Publication types

Comparative Study

MeSH terms

Administration, Oral
Animals
Biological Availability
Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
Glycine Plasma Membrane Transport Proteins / metabolism
Humans
Male
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Rats
Rats, Sprague-Dawley
Sulfonamides / administration & dosage*
Sulfonamides / chemistry*
Sulfonamides / metabolism
Triazoles / administration & dosage
Triazoles / chemical synthesis

Substances

Glycine Plasma Membrane Transport Proteins
SLC6A9 protein, human
Sulfonamides
Triazoles