New anthranilic acid based antagonists with high affinity and selectivity for the human cholecystokinin receptor 1 (hCCK1-R)

J Med Chem. 2011 Aug 25;54(16):5769-85. doi: 10.1021/jm200438b. Epub 2011 Jul 20.

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.

MeSH terms

  • Aminobutyrates / chemistry
  • Aminobutyrates / metabolism
  • Aminobutyrates / pharmacology*
  • Animals
  • Binding Sites / genetics
  • Binding, Competitive
  • COS Cells
  • Cerebral Cortex / metabolism
  • Chlorocebus aethiops
  • Gallbladder / drug effects
  • Gallbladder / physiology
  • Guinea Pigs
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / metabolism
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • In Vitro Techniques
  • Indoles / chemistry
  • Indoles / metabolism
  • Indoles / pharmacology
  • Male
  • Models, Molecular
  • Molecular Structure
  • Muscle Contraction / drug effects
  • Mutagenesis, Site-Directed
  • Mutation
  • Pancreas / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cholecystokinin A / antagonists & inhibitors*
  • Receptor, Cholecystokinin A / genetics
  • Receptor, Cholecystokinin A / metabolism
  • Sincalide / metabolism
  • Sincalide / pharmacology
  • Structure-Activity Relationship
  • ortho-Aminobenzoates / chemistry*
  • ortho-Aminobenzoates / metabolism
  • ortho-Aminobenzoates / pharmacology*

Substances

  • 2-(2-((1H-indole-2-carbonyl)amino)benzoylamino)-4-phenylbutyric acid
  • Aminobutyrates
  • Heterocyclic Compounds
  • Indoles
  • Receptor, Cholecystokinin A
  • VL-0395
  • ortho-Aminobenzoates
  • anthranilic acid
  • Sincalide