Abstract
A high throughput screening approach to the identification of selective cholecystokinin-2 receptor (CCK-2R) ligands resulted in the discovery of a novel series of antagonists, represented by 1-[2-[(2,1,3-benzothiadiazol-4-ylsulfonyl)amino]-5-chlorobenzoyl]-piperidine (1; CCK-2R, pK(I) = 6.4). Preliminary exploration of the structure-activity relationships around the anthranilic ring and the amide and sulfonamide moieties led to a nearly 50-fold improvement of receptor affinity and showed a greater than 1000-fold selectivity over the related cholecystokinin-1 receptor. Pharmacokinetic evaluation led to the identification of 4-[4-iodo-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-morpholine, 26d, a compound that demonstrates promising pharmacokinetic properties in the rat and dog with respect to plasma clearance and oral bioavailability and is a potent inhibitor in vivo of pentagastrin-stimulated acid secretion in the rat when dosed orally.
MeSH terms
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Animals
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Binding, Competitive
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Biological Availability
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Dogs
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Drug Stability
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Gallbladder / drug effects
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Gallbladder / physiology
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Gastric Acid / metabolism
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Guinea Pigs
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Humans
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In Vitro Techniques
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Male
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Microsomes, Liver / metabolism
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Morpholines / chemical synthesis*
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Morpholines / chemistry
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Morpholines / pharmacology
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Muscle Contraction
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Quinoxalines / chemical synthesis*
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Quinoxalines / chemistry
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Quinoxalines / pharmacology
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Radioligand Assay
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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 B / antagonists & inhibitors*
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Stereoisomerism
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Stomach / drug effects
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Stomach / physiology
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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ortho-Aminobenzoates / chemical synthesis*
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ortho-Aminobenzoates / chemistry
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ortho-Aminobenzoates / pharmacology
Substances
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4-(4-iodo-2-((5-quinoxalinylsulfonyl)amino)benzoyl)morpholine
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Morpholines
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Quinoxalines
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Receptor, Cholecystokinin A
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Receptor, Cholecystokinin B
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Sulfonamides
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ortho-Aminobenzoates