Abstract
The anthranilic acid diamides represent the most recent class of nonpeptide CCK(1) receptor (CCK(1)-R) antagonists. Herein we describe the second phase of the anthranilic acid C-terminal optimization using nonproteinogenic amino acids containing a phenyl ring in their side chain. The Homo-Phe derivative 2 (VL-0797) enhanced 12-fold the affinity for the rat CCK(1)-R affinity and 15-fold for the human CCK(1)-R relative to the reference compound 12 (VL-0395). The eutomer of 2 (6) exhibited a nanomolar range affinity toward the human CCK(1)-R and was at least 400-fold selective for the CCK(1)-R over the CCK(2)-R. Molecular docking in the modeled CCK(1)-R and its validation by site-directed mutagenesis experiments showed that the 6 binding site overlaps that occupied by the C-terminal bioactive region of the natural agonist CCK. Owing to their interesting properties, new compounds provided by this study represent a solid basis for further advances aimed at synthesis of clinically valuable CCK(1)-R antagonists.
© 2011 American Chemical Society
MeSH terms
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Aminobutyrates / chemistry
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Aminobutyrates / metabolism
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Aminobutyrates / pharmacology*
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Animals
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Binding Sites / genetics
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Binding, Competitive
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COS Cells
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Cerebral Cortex / metabolism
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Chlorocebus aethiops
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Gallbladder / drug effects
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Gallbladder / physiology
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Guinea Pigs
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Heterocyclic Compounds / chemistry
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Heterocyclic Compounds / metabolism
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Heterocyclic Compounds / pharmacology*
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Humans
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In Vitro Techniques
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Indoles / chemistry
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Indoles / metabolism
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Indoles / pharmacology
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Male
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Models, Molecular
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Molecular Structure
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Muscle Contraction / drug effects
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Mutagenesis, Site-Directed
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Mutation
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Pancreas / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptor, Cholecystokinin A / antagonists & inhibitors*
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Receptor, Cholecystokinin A / genetics
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Receptor, Cholecystokinin A / metabolism
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Sincalide / metabolism
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Sincalide / pharmacology
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Structure-Activity Relationship
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ortho-Aminobenzoates / chemistry*
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ortho-Aminobenzoates / metabolism
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ortho-Aminobenzoates / pharmacology*
Substances
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2-(2-((1H-indole-2-carbonyl)amino)benzoylamino)-4-phenylbutyric acid
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Aminobutyrates
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Heterocyclic Compounds
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Indoles
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Receptor, Cholecystokinin A
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VL-0395
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ortho-Aminobenzoates
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anthranilic acid
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Sincalide