Abstract
A series of pyrrolopyridinones was designed and synthesized as constrained analogs of the pyrazole CB-1 antagonist rimonabant. Certain examples exhibited very potent hCB-1 receptor binding affinity and functional antagonism with Ki and Kb values below 10 nM, and with high selectivity for CB-1 over CB-2 (>100-fold). A representative analog was established to cause significant appetite suppression and reduction in body weight gain in industry-standard rat models used to develop new therapeutics for obesity.
MeSH terms
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Animals
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Anti-Obesity Agents / chemical synthesis*
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Anti-Obesity Agents / pharmacokinetics
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Anti-Obesity Agents / pharmacology*
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Body Weight / drug effects
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Crystallography, X-Ray
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Drug Design
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Eating / drug effects
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Humans
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Magnetic Resonance Spectroscopy
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Male
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Models, Molecular
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Obesity / drug therapy
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Piperidines / chemical synthesis*
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Piperidines / pharmacology*
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacology*
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Pyridones / chemical synthesis*
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Pyridones / pharmacokinetics
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Pyridones / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology
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Rats
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Rats, Wistar
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Rats, Zucker
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Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
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Rimonabant
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Structure-Activity Relationship
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Weight Gain / drug effects
Substances
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1,5,6,7-Tetrahydro-4H-pyrrolo(3,2-c)pyridine-4-one
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Anti-Obesity Agents
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Piperidines
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Pyrazoles
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Pyridones
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Pyrroles
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Receptor, Cannabinoid, CB1
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Rimonabant