title: JNJ-26070109 [(R)4-bromo-N-[1-(2,4-difluoro-phenyl)-ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide]: a novel, potent, and selective cholecystokinin 2 receptor antagonist with good oral bioavailability.
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 (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, ∼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 (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 μM, respectively. Overall, we have demonstrated that JNJ-26070109 is a high-affinity, selective CCK2 receptor antagonist with good pharmacokinetic properties.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, LLC San Diego, California 92101, USA.
authors.forename: Magda F
authors.initials: MF
authors.lastname: Morton
authors.forename: Terrance D
authors.initials: TD
authors.lastname: Barrett
authors.forename: Jamie
authors.initials: J
authors.lastname: Freedman
authors.forename: Lina
authors.initials: L
authors.lastname: Li
authors.forename: Michele C
authors.initials: MC
authors.lastname: Rizzolio
authors.forename: Clodagh E
authors.initials: CE
authors.lastname: Prendergast
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wu
authors.forename: Veronica
authors.initials: V
authors.lastname: Moreno
authors.forename: Jayashree
authors.initials: J
authors.lastname: Pyati
authors.forename: Katherine
authors.initials: K
authors.lastname: Figueroa
authors.forename: Laurence
authors.initials: L
authors.lastname: Cagnon
authors.forename: Guy
authors.initials: G
authors.lastname: Lagaud
authors.forename: Luc
authors.initials: L
authors.lastname: Ver Donck
authors.forename: Etienne
authors.initials: E
authors.lastname: Ghoos
authors.forename: Brett
authors.initials: B
authors.lastname: Allison
authors.forename: Michael H
authors.initials: MH
authors.lastname: Rabinowitz
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Shankley
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001570:Benzodiazepinones / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D001682:Biological Availability; D016466:CHO Cells; D018938:Caco-2 Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D011810:Quinoxalines / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013045:Species Specificity; D013449:Sulfonamides / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism
chemical_list: C560626:4-bromo-N-(1-(2,4-difluoro-phenyl)ethyl)-2-(quinoxaline-5-sulfonylamino)benzamide; D001570:Benzodiazepinones; D010671:Phenylurea Compounds; D011810:Quinoxalines; D043887:Receptor, Cholecystokinin B; D013449:Sulfonamides; C104428:YF 476