Discovery of N-{[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]methyl}benzamides as novel, selective and potent GlyT1 inhibitors

Zhijian Zhao; William H Leister; Julie A O'Brien; Wei Lemaire; David L Williams Jr; Marlene A Jacobson; Cyrille Sur; Gene G Kinney; Doug J Pettibone; Philip R Tiller; Sheri Smith; George D Hartman; Craig W Lindsley; Scott E Wolkenberg

doi:10.1016/j.bmcl.2008.12.115

Discovery of N-{[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]methyl}benzamides as novel, selective and potent GlyT1 inhibitors

Bioorg Med Chem Lett. 2009 Mar 1;19(5):1488-91. doi: 10.1016/j.bmcl.2008.12.115. Epub 2009 Jan 9.

Authors

Zhijian Zhao¹, William H Leister, Julie A O'Brien, Wei Lemaire, David L Williams Jr, Marlene A Jacobson, Cyrille Sur, Gene G Kinney, Doug J Pettibone, Philip R Tiller, Sheri Smith, George D Hartman, Craig W Lindsley, Scott E Wolkenberg

Affiliation

¹ Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck & Co., Inc., WP-14-1, PO Box 4 Sumneytown Pike, West Point, PA 19486, USA.

PMID: 19179073
DOI: 10.1016/j.bmcl.2008.12.115

Abstract

Employing an iterative analogue library approach, novel potent and selective glycine transporter 1 (GlyT1) inhibitors containing a 4-pyridin-2-ylpiperidine sulfonamide have been discovered. These inhibitors are devoid of time-dependent CYP inhibition activity and exhibit improved aqueous solubility versus the corresponding 4-phenylpiperidine analogues.

Publication types

Comparative Study

MeSH terms

Benzamides / chemical synthesis*
Benzamides / pharmacology
Drug Discovery / methods*
Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
Glycine Plasma Membrane Transport Proteins / metabolism
Humans
Piperidines / chemical synthesis*
Piperidines / pharmacology
Solubility
Sulfonamides / chemical synthesis*
Sulfonamides / pharmacology

Substances

Benzamides
Glycine Plasma Membrane Transport Proteins
Piperidines
SLC6A9 protein, human
Sulfonamides