Satoh M, Kondoh Y, Okamoto Y, Nishida A, Miyata K, Ohta M, Mase T, Murase K
Neuroscience-Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Tsukuba City, Ibaraki, Japan.
Chem Pharm Bull (Tokyo). 1995 Dec;43(12):2159-67. doi: 10.1248/cpb.43.2159.
A novel series of 1-aroylmethyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one derivatives was prepared and evaluated for activity as gastrin/cholecystokinin (CCK)-B receptor antagonists. In vitro binding studies showed that some derivatives exhibited potent affinity for gastrin CCK-B receptor and high selectivity over peripheral CCK(CCK-A) receptor. Furthermore these compounds potently inhibited pentagastrin-induced gastric acid secretion upon intravenous administration in an in vivo model in rats. Structure-activity relationship studies of this series suggested that 1-[(R)-2,3-dihydro-1-(2,3-dihydro-1-(2-methylphenacyl)-2-oxo-5-phe nyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (35b, YM022) was the optimal compound with IC50 values of 0.17, 0.11 and 150 nM for gastrin, CCK-B and CCK-A receptors, respectively, and an ED50 value of 9.5 nmol/kg (i.v.) in rats. The absolute configuration of the precursor of YM022, an (R)-3-amino-1,3-dihydro-2H-1,4-benzodiazepin-2-one derivative ((R)-25), was determined by X-ray crystallographic analysis of its (S) mandelate. It would be expected that YM022, a potent and selective gastrin CCK-B receptor antagonist, inhibits gastric acid secretion without inducing gastrin-mediated side effects such as hypergastrinemia and hyperplasia of oxyntic mucosa.
制备了一系列新型的1-芳酰甲基-1,3-二氢-2H-1,4-苯并二氮杂卓-2-酮衍生物，并对其作为胃泌素/胆囊收缩素（CCK）-B受体拮抗剂的活性进行了评估。体外结合研究表明，一些衍生物对胃泌素CCK-B受体表现出强效亲和力，并且对外周CCK（CCK-A）受体具有高选择性。此外，在大鼠体内模型中静脉给药时，这些化合物能有效抑制五肽胃泌素诱导的胃酸分泌。该系列的构效关系研究表明，1-[(R)-2,3-二氢-1-(2,3-二氢-1-(2-甲基苯甲酰基)-2-氧代-5-苯基-1H-1,4-苯并二氮杂卓-3-基]-3-(3-甲基苯基)脲（35b，YM022）是最佳化合物，对胃泌素、CCK-B和CCK-A受体的IC50值分别为0.17、0.11和150 nM，在大鼠体内的ED50值为9.5 nmol/kg（静脉注射）。通过对其(S)-扁桃酸盐进行X射线晶体学分析，确定了YM022的前体，即(R)-3-氨基-1,3-二氢-2H-1,4-苯并二氮杂卓-2-酮衍生物((R)-25)的绝对构型。预计强效且选择性的胃泌素CCK-B受体拮抗剂YM022能抑制胃酸分泌，而不会引发胃泌素介导的副作用，如高胃泌素血症和胃黏膜增生。
