Semple G, Ryder H, Rooker D P, Batt A R, Kendrick D A, Szelke M, Ohta M, Satoh M, Nishida A, Akuzawa S, Miyata K
Ferring Research Institute, Chilworth Research Centre, Chilworth, Southampton, U.K.
J Med Chem. 1997 Jan 31;40(3):331-41. doi: 10.1021/jm960669+.
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 vivo 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-pyri dyl) -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 21nmol/kg po in dogs. 15c is currently under clinical investigation for the treatment of gastro-oesophagal reflux disease (GORD).
已合成了一系列基于1,4 - 苯二氮䓬 - 2 - 酮的新型胃泌素/CCK - B受体拮抗剂，它们与原型类似物L - 365,260相关，且与最近报道的化合物YM022关系更为密切，并对其生物活性进行了评估。筛选这些化合物抑制[125I]CCK - 8与大鼠脑制备的胃泌素/CCK - B受体结合的能力，以及[3H]L - 364,718与大鼠胰腺CCK - A受体结合的能力，结果表明它们是胃泌素/CCK - B受体的强效和选择性配体。体内功能研究表明这些化合物是该受体的拮抗剂，这可通过它们抑制麻醉大鼠中五肽胃泌素诱导的胃酸分泌的能力得到证明。更广泛的体内评估包括测定选定化合物在大鼠胃酸分泌模型中的ED50值，以及检查这些化合物经口服和静脉给药后对海登海因小胃犬中五肽胃泌素诱导的胃酸分泌的影响。两种化合物，即(3R)-N-[1-[(叔丁基羰基)甲基]-2,3 - 二氢 - 2 - 氧代 - 5 - (2 - 吡啶基)-1H - 1,4 - 苯二氮䓬 - 3 - 基]-N'-[3-(甲氨基)苯基]脲，15c（YF476），和(3R)-N-[1-[(叔丁基羰基)甲基]-2,3 - 二氢 - 2 - 氧代 - 5 - (2 - 吡啶基)-1H - 1,4 - 苯二氮䓬 - 3 - 基]-N'-[3-(二甲氨基)苯基]脲盐酸盐，15d，在两种模型中均显示出强效的剂量依赖性效应，前者在犬中显示出优异的口服生物利用度且口服ED50为21nmol/kg。15c目前正在进行治疗胃食管反流病（GORD）的临床研究。
