Abstract
A series of alkylidene hydrazide derivatives containing an alkoxyaryl moiety was optimized. The resulting hydrazide-ethers were competitive antagonists at the human glucagon receptor. Pharmacokinetic experiments showed fast clearance of most of the compounds tested. A representative compound [4-hydroxy-3-cyanobenzoic acid (4-isopropylbenzyloxy-3,5-dimethoxymethylene)hydrazide] with an IC50 value of 20 nM was shown to reduce blood glucose levels in fasted rats.
MeSH terms
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Animals
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Binding, Competitive
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Blood Glucose / drug effects
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Humans
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Hydrazines / administration & dosage
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Hydrazines / chemical synthesis*
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Hydrazines / pharmacokinetics*
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Hypoglycemic Agents / administration & dosage
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / pharmacokinetics
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Inhibitory Concentration 50
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Injections
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Metabolic Clearance Rate
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Microsomes, Liver / metabolism
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Rats
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Receptors, Glucagon / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Blood Glucose
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Hydrazines
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Hypoglycemic Agents
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Receptors, Glucagon