Abstract
JNJ-26070109 [(R)4-bromo-N-[1-(2,4-difluoro-phenyl)-ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide] is a representative of a new chemical class of competitive antagonists of cholecystokinin 2 (CCK2) receptors. In this study, the primary in vitro pharmacology of JNJ-26070109 was evaluated along with the pharmacokinetic and pharmacodynamic properties of this compound in rat and canine models of gastric acid secretion. JNJ-26070109 expressed high affinity for human (pKI = 8.49 ± 0.13), rat (pKI = 7.99 ± 0.08), and dog (pKI = 7.70 ± 0.14) CCK2 receptors. The selectivity of JNJ-26070109 at the CCK2 receptor versus the CCK1 receptor was species-dependent, with the greatest degree of selectivity (>1200-fold) measured at the human isoforms of the CCK1 receptor (selectivity at CCK2 versus CCK1 receptors: human, ∼1222-fold; rat, ∼324-fold; dog ∼336-fold). JNJ-26070109 behaved as a surmountable, competitive, antagonist of human CCK2 receptors in a calcium mobilization assay (pKB = 8.53 ± 0.05) and in pentagastrin-stimulated gastric acid secretion in the isolated, lumen-perfused, mouse stomach assay (pKB = 8.19 ± 0.13). The pharmacokinetic profile of this compound was determined in vivo in rats and dogs. JNJ-26070109 was shown to have high oral bioavailability (%F rat = 73 ± 16; %F dog = 92 ± 12) with half lives of 1.8 ± 0.3 and 1.2 ± 0.1 h in rat and dog, respectively. The pharmacodynamic properties of this compound were investigated using two in vivo models. In conscious rat and dog chronic gastric fistula models of pentagastrin-stimulated acid secretion, JNJ-26070109 had oral EC50 values of 1.5 and 0.26 μM, respectively. Overall, we have demonstrated that JNJ-26070109 is a high-affinity, selective CCK2 receptor antagonist with good pharmacokinetic properties.
Footnotes
This work was supported by Johnson & Johnson Pharmaceutical Research and Development L.L.C.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.178483.
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ABBREVIATIONS:
- CCK
- cholecystokinin
- E/[A]
- concentration-effect
- JNJ-26070109
- (R)4-bromo-N-[1-(2,4-difluoro-phenyl)-ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide
- HEKZFP
- human embryonic kidney zinc finger protein
- CCK-8S
- sulfated cholecystokinin octapeptide
- FLIPR
- fluorometric imaging plate reader
- YF476
- (R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2′-pyridyl)-1H-1,4-benzodiazepin-3-yl]-3-(3-methyl-phenyl)urea
- L-365,260
- N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea
- YM022
- 1-(2,3-dihydro-1-(2′-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-(3-methylphenyl)urea
- PD-134,308
- 4-[[(1R)-2-[[(2R)-3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid
- JB93182
- 5-[[(2S)-2-[[6-(1-adamantylmethylcarbamoyl)1H-indole-5-carbonyl]amino]-3-phenylpropanoyl]amino]benzene-1,3-dicarboxylic acid
- JB95008
- 5-[[(2S)-2-[[[5-[[(cycloheptylmethyl)amino]carbonyl]-1H-benzimidazol-6-yl]carbonyl]amino]-3-(2-fluorophenyl)-1-oxopropyl]amino]-1,3-benzenedicarboxylic acid
- L-364,718
- N-[(3S)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-1H-indole-2-carboxamide.
- Received December 21, 2010.
- Accepted March 29, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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