RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 328
OP 336
DO 10.1124/jpet.110.178483
VO 338
IS 1
A1 Magda F. Morton
A1 Terrance D. Barrett
A1 Jamie Freedman
A1 Lina Li
A1 Michele C. Rizzolio
A1 Clodagh E. Prendergast
A1 Xiaodong Wu
A1 Veronica Moreno
A1 Jayashree Pyati
A1 Katherine Figueroa
A1 Laurence Cagnon
A1 Guy Lagaud
A1 Luc Ver Donck
A1 Etienne Ghoos
A1 Brett Allison
A1 Michael H. Rabinowitz
A1 Nigel P. Shankley
YR 2011
UL http://jpet.aspetjournals.org/content/338/1/328.abstract
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 (&gt;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.