Abstract
A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.
MeSH terms
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ATP-Binding Cassette Transporters / metabolism
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Administration, Oral
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Amides / chemical synthesis*
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Amides / pharmacology
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Animals
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Benzofurans / chemical synthesis*
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Benzofurans / pharmacology
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Brain / metabolism
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Cerebrospinal Fluid / metabolism
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Drug Stability
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Eating / drug effects
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Rats
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Receptors, Neuropeptide Y / antagonists & inhibitors*
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / pharmacology
Substances
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ATP-Binding Cassette Transporters
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Amides
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Benzofurans
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Receptors, Neuropeptide Y
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Spiro Compounds
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neuropeptide Y5 receptor
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benzofuran