JNJ-26070109 ((R)4-bromo-N-(1-(2,4-difluoro-phenyl)-ethyl)-2-(quinoxaline-5-sulfonylamino)-ben zamide): a novel, potent, and selective cholecystokinin 2 receptor antagonist with good oral bioavailability.

摘要

JNJ-26070109 [(R)4-bromo-N-[1-(2,4-difluoro-phenyl)-ethyl]-2-(quinoxaline-5-sulfonylamino)-ben zamide] 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 (pK(I) = 8.49 +/- 0.13), rat (pK(I) = 7.99 +/- 0.08), and dog (pK(I) = 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, approximately 1222-fold; rat, approximately 324-fold; dog approximately 336-fold). JNJ-26070109 behaved as a surmountable, competitive, antagonist of human CCK2 receptors in a calcium mobilization assay (pK(B) = 8.53 +/- 0.05) and in pentagastrin-stimulated gastric acid secretion in the isolated, lumen-perfused, mouse stomach assay (pK(B) = 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 EC(50) values of 1.5 and 0.26 muM, respectively. Overall, we have demonstrated that JNJ-26070109 is a high-affinity, selective CCK2 receptor antagonist with good pharmacokinetic properties.