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
| Autor: | Nigel P. Shankley, Clodagh Prendergast, Luc Ver Donck, Lina Li, E. Ghoos, Michele C. Rizzolio, Terrance D. Barrett, Jamie M. Freedman, Magda F. Morton, Katherine W. Figueroa, Laurence Cagnon, Xiaodong Wu, Brett D. Allison, Veronica Moreno, Guy Lagaud, Michael H. Rabinowitz, Jayashree Pyati |
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| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty Guinea Pigs Administration Oral Biological Availability CHO Cells Pharmacology Rats Sprague-Dawley chemistry.chemical_compound Mice Cricetulus Dogs Species Specificity In vivo Internal medicine Cricetinae Quinoxalines medicine Animals Humans Receptor Benzamide Cholecystokinin Benzodiazepinones Sulfonamides Dose-Response Relationship Drug Chemistry Phenylurea Compounds Antagonist Receptor Cholecystokinin B Bioavailability Rats Endocrinology Cholecystokinin B receptor Molecular Medicine Gastric acid Female Caco-2 Cells |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 338(1) |
| ISSN: | 1521-0103 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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