PT  - JOURNAL ARTICLE
AU  - Magda F. Morton
AU  - Terrance D. Barrett
AU  - Jamie Freedman
AU  - Lina Li
AU  - Michele C. Rizzolio
AU  - Clodagh E. Prendergast
AU  - Xiaodong Wu
AU  - Veronica Moreno
AU  - Jayashree Pyati
AU  - Katherine Figueroa
AU  - Laurence Cagnon
AU  - Guy Lagaud
AU  - Luc Ver Donck
AU  - Etienne Ghoos
AU  - Brett Allison
AU  - Michael H. Rabinowitz
AU  - Nigel P. Shankley
TI  - JNJ-26070109 [(<em>R</em>)4-Bromo-<em>N</em>-[1-(2,4-difluoro-phenyl)-ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide]: A Novel, Potent, and Selective Cholecystokinin 2 Receptor Antagonist with Good Oral Bioavailability
AID  - 10.1124/jpet.110.178483
DP  - 2011 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 328--336
VI  - 338
IP  - 1
4099  - http://jpet.aspetjournals.org/content/338/1/328.short
4100  - http://jpet.aspetjournals.org/content/338/1/328.full
SO  - J Pharmacol Exp Ther2011 Jul 01; 338
AB  - 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.