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 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 CCK receptors (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 h 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 μ M and 0.26 μ M, respectively. Overall, we have demonstrated that JNJ-26070109 is a high affinity, selective, CCK2 receptor antagonist with good pharmacokinetic properties.
- Received December 21, 2010.
- Revision received March 29, 2011.
- Accepted March 29, 2011.
- The American Society for Pharmacology and Experimental Therapeutics