Abstract
A series of 2-pyridone-containing imidazoline derivatives was synthesized and evaluated as neuropeptide Y Y5 receptor antagonists. Optimization of the 2-pyridone structure on the 2-position of the imidazoline ring led to identification of 1-(difluoromethyl)-5-[(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl]pyridin-2(1H)-one (7m). Compound 7m displayed statistically significant inhibition of food intake in an agonist-induced food intake model in SD rats and no adverse cardiovascular effects in anesthetized dogs. In addition, markedly higher brain penetrability and a lower plasma Occ90 value were observed in P-gp-deficient mdr1a (-/-) mice compared to mdr1a (+/+) mice after oral administration of 7m.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / deficiency
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Animals
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Anti-Obesity Agents / chemical synthesis
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Anti-Obesity Agents / chemistry*
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Anti-Obesity Agents / pharmacokinetics
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Dogs
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Drug Discovery
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Humans
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Imidazolines / chemical synthesis
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Imidazolines / chemistry*
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Imidazolines / pharmacokinetics
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Mice
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Pyridones / chemical synthesis
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Pyridones / chemistry*
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Pyridones / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, Neuropeptide Y / antagonists & inhibitors*
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Receptors, Neuropeptide Y / metabolism
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Structure-Activity Relationship
Substances
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1-(difluoromethyl)-5-((4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2(1H)-one
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Anti-Obesity Agents
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Imidazolines
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Pyridones
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Receptors, Neuropeptide Y
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neuropeptide Y5 receptor