Abstract
Targeting glycosphingolipid synthesis has emerged as a novel approach for treating metabolic diseases. 32 (EXEL-0346) represents a new class of glucosylceramide synthase (GCS) inhibitors. This report details the elaboration of hit 8 with the goal of achieving and maintaining maximum GCS inhibition in vivo. 32 inhibited GCS with an IC(50) of 2 nM and achieved maximum hepatic GCS inhibition after four or five daily doses in rodents. Robust improvements in glucose tolerance in DIO mice and ZDF rats were observed after 2 weeks of q.d. dosing. Four weeks of dosing resulted in decreased plasma triglycerides and reduced hepatic fat deposition. Thus, 32 provides insight into the amount of metabolic regulation that can be restored following achievement of maximal target knockdown.
MeSH terms
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Adipose Tissue, White / drug effects
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Adipose Tissue, White / metabolism
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Animals
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Diabetes Mellitus, Type 2 / drug therapy
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Diabetes Mellitus, Type 2 / enzymology
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Female
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Gangliosides / metabolism
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Glucose Tolerance Test
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Glucosyltransferases / antagonists & inhibitors*
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Glucosyltransferases / metabolism
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Humans
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Liver / drug effects
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Liver / enzymology
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Magnetic Resonance Spectroscopy
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Mass Spectrometry
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Mice
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Mice, Inbred C57BL
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Mice, Nude
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Phenylalanine / analogs & derivatives*
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Phenylalanine / pharmacology
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Rats
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Rats, Sprague-Dawley
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Rats, Zucker
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Structure-Activity Relationship
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Triglycerides / blood
Substances
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Enzyme Inhibitors
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Gangliosides
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Triglycerides
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Phenylalanine
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Glucosyltransferases
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ceramide glucosyltransferase