- BEZAMIDE DERIVATIVES FOR THE TREATMENT OF DISEASES MEDIATED BY CYTOKINES
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The invention concerns the use of amide derivatives of formula (I) wherein: R1 and R2 are substituents such as hydroxy, C1-6alkoxy, mercapto, C1-6alkylthio, amino, C1-6alkylamino and di-(C1-6alkyl)amino; m and p are independently 0-3; R3 is C1-4alkyl; q is 0-4; and R4 is aryl or cycloalkyl; or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by cytokines
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- (3R)-N-(1-(tert-butylcarbonylmethyl)-2,3-dihydro-2-oxo-5-(2-pyridyl)- 1H-1,4-benzodiazepin-3-yl)-N'-(3-(methylamino)phenyl)urea (YF476): A potent and orally active gastrin/CCK-B antagonist
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A number of new 1,4-benzodiazepin-2-one-based gastrin/CCK-B receptor antagonists related to the archetypal analogue L-365,260, and more closely to the recently reported compound YM022, have been synthesized and evaluated for biological activity. The compounds were screened for their ability to inhibit the binding of [125I]CCK-8 to gastrin/CCK-B receptors prepared from rat brains and that of [3H]L-364,718 to CCK-A receptors from rat pancreas, and were shown to be potent and selective ligands for the gastrin/CCK-B receptor. Functional studies in vivo demonstrated the compounds to be antagonists of the receptor as evidenced by their ability to inhibit pentagastrin-induced gastric acid secretion in anesthetized rats. More extensive evaluation in viva included determination of ED50 values in the rat acid secretion model for selected compounds and an examination of the effect of these compounds on pentagastrin-induced gastric acid secretion in Heidenhain pouch dogs following oral and intravenous administration. Two compounds, i.e. (3R)-N- [1-[(tert-butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4- benzodiazepin-3-yl]-N'-[3-(methylamino)phenyl]urea, 15c (YF476), and (3R)-N- [1-[(tert-Butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4- benzodiazepin-3-yl]-N'-[3-(dimethylamino)phenyl]urea hydrochloride, 15d, showed potent dose-dependent effects in both models with the former showing excellent oral bioavailability and an ED50 of 21 nmol/kg po in dogs. 15e is currently under clinical investigation for the treatment of gastro-oesophagal reflux disease (GORD).
- Semple, Graeme,Ryder, Hamish,Rooker, David P.,Batt, Andrzej R.,Kendrick, David A.,Szelke, Michael,Ohta, Mitsuaki,Satoh, Masato,Nishida, Akito,Akuzawa, Shinobu,Miyata, Keiji
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p. 331 - 341
(2007/10/03)
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