Structure activity relationship studies on chemically non-reactive glycine sulfonamide inhibitors of diacylglycerol lipase

Louis S Chupak; Xiaofan Zheng; Shuanghua Hu; Yazhong Huang; Min Ding; Martin A Lewis; Ryan S Westphal; Yuval Blat; Andrea McClure; Robert G Gentles

doi:10.1016/j.bmc.2016.02.006

Structure activity relationship studies on chemically non-reactive glycine sulfonamide inhibitors of diacylglycerol lipase

Bioorg Med Chem. 2016 Apr 1;24(7):1455-68. doi: 10.1016/j.bmc.2016.02.006. Epub 2016 Feb 16.

Authors

Affiliations

¹ Discovery Chemistry, Research and Development, Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: louis.chupak@bms.com.
² Discovery Chemistry, Research and Development, Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, USA.
³ Neuroscience Biology, Disease Sciences and Biologics, Research and Development, Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, USA.
⁴ Lead Evaluation, Discovery, Research and Development, Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, USA.
⁵ Discovery Chemistry Platforms, Research and Development, Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492, USA.

PMID: 26917221
DOI: 10.1016/j.bmc.2016.02.006

Abstract

N-Benzylic-substituted glycine sulfonamides that reversibly inhibit diacylglycerol (DAG) lipases are reported. Detailed herein are the structure activity relationships, profiling characteristics and physico-chemical properties for the first reported series of DAG lipase (DAGL) inhibitors that function without covalent attachment to the enzyme. Highly potent examples are presented that represent valuable tool compounds for studying DAGL inhibition and constitute important leads for future medicinal chemistry efforts.

Keywords: 2-Arachidonoylglycerol; Diacylglycerol; Endocannabinoid; Glycine; Lipase inhibitor; Sulfonamide.

MeSH terms

Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Glycine / analogs & derivatives
Glycine / chemistry
Glycine / pharmacology*
Humans
Lipoprotein Lipase / antagonists & inhibitors*
Lipoprotein Lipase / metabolism
Molecular Structure
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

Enzyme Inhibitors
Sulfonamides
Lipoprotein Lipase
Glycine