152665-63-9

Upstream product

• 2835-77-0 (2-aminophenyl)(phenyl)methanone 
• 161365-74-8 benzyl N-[[(2-benzoylphenyl)carbamoyl](1H-1,2,3-benzotriazol-1-yl)methyl]carbamate 
• 124676-19-3 2-(benzotriazol-1-yl)-N-(benzyloxycarbonyl)glycine 
• 108895-98-3 benzyl 2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate 
• 5469-26-1 1-Bromopinacolon 

Downstream Products

• 155412-24-1 (R)-3-Amino-1-(3,3-dimethyl-2-oxo-butyl)-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 

Relevant academic research and scientific papers

(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

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).

Synthesis and biological activity of 5-heteroaryl benzodiazepines: Analogues of YM022

A novel series of analogues of the potent gastrin/CCK-B receptor antagonist YM022 have been prepared which incorporate 5- and 6-membered heteroaromatic rings in the benzodiazepine 5-position. The 5-(2-pyridyl) derivatives in particular retained good in vitro and in vivo potency and one such compound 9i was shown to inhibit acid secretion after oral dosing in dogs. Improved bioavailability for 9i over the 5-phenyl analogue, 9h was demonstrated in rats.

Synthesis and biological activity of 1-alkylcarbonylmethyl analogues of YM022

A novel series of 1-alkylcarbonylmethyl analogues of the potent gastrin/CCK-B receptor antagonist YM022 have been prepared. A number of analogues retained good affinity for the gastrin/CCK-B receptor and one compound (6d) showed improved binding and enhanced selectivity for this receptor over CCK-A. A second compound (6j) gave improved in vivo inhibition of gastric acid secretion in rats. Both analogues were shown to have significantly better activity in the same model following i.d. dosing than either YM022 or L-365,260.