Abstract
Starting from a known piperazine-based SCD-1 inhibitor, we obtained more potent benzoylpiperidine analogs. Optimization of the structure of the benzoylpiperidine-based SCD-1 inhibitors resulted in the identification of 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-yl-ethyl)amide (24) which showed strong inhibitory activity against both human and murine SCD-1. In addition, this compound exhibited good oral bioavailability and demonstrated plasma triglyceride lowering effects in Zucker fatty rats in a dose-dependent manner after a 7-day oral administration (qd).
Copyright 2009 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Humans
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Hypoglycemic Agents / chemical synthesis
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Hypoglycemic Agents / chemistry*
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Hypoglycemic Agents / pharmacokinetics
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Mice
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Microsomes, Liver / metabolism
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Piperidines / chemical synthesis
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Piperidines / chemistry*
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Piperidines / pharmacokinetics
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Pyridazines / chemical synthesis
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Pyridazines / chemistry*
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Pyridazines / pharmacology
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Pyridines / chemical synthesis
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Pyridines / chemistry*
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Pyridines / pharmacology
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Rats
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Rats, Zucker
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Stearoyl-CoA Desaturase / antagonists & inhibitors*
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Stearoyl-CoA Desaturase / metabolism
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Triglycerides / blood*
Substances
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6-(4-(2-methylbenzoyl)piperidin-1-yl)pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-ylethyl)amide
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Enzyme Inhibitors
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Hypoglycemic Agents
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Piperidines
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Pyridazines
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Pyridines
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Triglycerides
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Stearoyl-CoA Desaturase