دورية أكاديمية
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.
| العنوان: | 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. |
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| المؤلفون: | Morton MF; Johnson & Johnson Pharmaceutical Research & Development, LLC San Diego, California 92101, USA., Barrett TD, Freedman J, Li L, Rizzolio MC, Prendergast CE, Wu X, Moreno V, Pyati J, Figueroa K, Cagnon L, Lagaud G, Ver Donck L, Ghoos E, Allison B, Rabinowitz MH, Shankley NP |
| المصدر: | The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2011 Jul; Vol. 338 (1), pp. 328-36. Date of Electronic Publication: 2011 Apr 14. |
| نوع المنشور: | Comparative Study; Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0376362 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0103 (Electronic) Linking ISSN: 00223565 NLM ISO Abbreviation: J Pharmacol Exp Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1999- : Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics Original Publication: Baltimore : Williams & Wilkins |
| مواضيع طبية MeSH: | Benzodiazepinones/*administration & dosage , Benzodiazepinones/*metabolism , Phenylurea Compounds/*administration & dosage , Phenylurea Compounds/*metabolism , Quinoxalines/*administration & dosage , Receptor, Cholecystokinin B/*antagonists & inhibitors , Receptor, Cholecystokinin B/*metabolism , Sulfonamides/*administration & dosage, Administration, Oral ; Animals ; Benzodiazepinones/chemistry ; Biological Availability ; CHO Cells ; Caco-2 Cells ; Cricetinae ; Cricetulus ; Dogs ; Dose-Response Relationship, Drug ; Female ; Guinea Pigs ; Humans ; Male ; Mice ; Phenylurea Compounds/chemistry ; Quinoxalines/chemistry ; Quinoxalines/metabolism ; Rats ; Rats, Sprague-Dawley ; Species Specificity ; Sulfonamides/chemistry ; Sulfonamides/metabolism |
| مستخلص: | 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. |
| المشرفين على المادة: | 0 (4-bromo-N-(1-(2,4-difluoro-phenyl)ethyl)-2-(quinoxaline-5-sulfonylamino)benzamide) 0 (Benzodiazepinones) 0 (Phenylurea Compounds) 0 (Quinoxalines) 0 (Receptor, Cholecystokinin B) 0 (Sulfonamides) HOU4I0G29C (YF 476) |
| تواريخ الأحداث: | Date Created: 20110416 Date Completed: 20110830 Latest Revision: 20181217 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1124/jpet.110.178483 |
| PMID: | 21493750 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-0103 |
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| DOI: | 10.1124/jpet.110.178483 |