(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

Abstract

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).

Synthesis of N-Substituted Piperazinyl Carbamoyl and Acetyl Derivatives of Tetrahydropapaverine: Potent Antispasmodic Agents.

“…10) Substituted ureas 11) have also been of recent interest due to appearance of this functionality in drug candidates such as human immunodeficiency virus (HIV) protease inhibitors, [12][13][14] FKBP12 inhibitors, 15) CCKB-receptor antagonists 16,17) and endothelin antagonists. 18) Recently, Okuyama et al have reported a novel Ca 2ϩ channel blocker T-477 [(R)-(ϩ)-2-(4-chlorophenyl)-2,3-dihydro-4-diethylaminoacetyl-4H-1,4-benzothiazine hydrochloride] which prevents brain edema in rats.…”

Haemodynamic and Exocrine Effects of Caerulein at Submaximal and Supramaximal Levels on the Rat Pancreas: Role of Cholecystokinin Receptor Subtypes

“…Separate groups of rats were pretreated subcutaneously with CCK receptor antagonists. Due to a limited supply of PD140548 and PD135158, these compounds had to be replaced by lorglumide (0.03-1 mol/kg [18] ) and YF476 (1 mol/kg [19] ) as antagonists for the CCK 1 and CCK 2 receptor, respectively. Control animals were injected subcutaneously with the vehicle, polyethylene glycol-300 (1 ml/kg).…”

Acid Suppression Therapy: Where Do We Go from Here?

“…YF-476 is a potent and orally active CCK 2 antagonist synthesized at Ferring Research Institute (Southampton, UK) [277] and co-developed with Yamanouchi Pharmaceutical Co. (Tsukuba, Japan). In vitro and vivo experiments [278,279] have confi rmed its high selectivity by showing that its affi nity for the rat brain CCK 2 receptors is 4,100 times higher than that for rat pancreatic CCK 1 receptors and that the drug is able to inhibit pentagastrinbut not histamine-stimulated acid secretion in rats and dogs.…”