Controlled modification of acidity in cholecystokinin B receptor antagonists: N-(1,4-benzodiazepin-3-yl)-N'-[3-(tetrazol-5-ylamino)phenyl]ureas

被引:87
作者
Castro, JL
Ball, RG
Broughton, HB
Russell, MGN
Rathbone, D
Watt, AP
Baker, R
Chapman, KL
Fletcher, AE
Patel, S
Smith, AJ
Marshall, GR
Ryecroft, W
Matassa, VG
机构
[1] MERCK SHARP & DOHME RES LABS, NEUROSCI RES CTR, DEPT BIOCHEM, HARLOW CM20 2QR, ESSEX, ENGLAND
[2] MERCK SHARP & DOHME RES LABS, NEUROSCI RES CTR, DEPT PHARMACOL, HARLOW CM20 2QR, ESSEX, ENGLAND
[3] MERCK RES LABS, DEPT BIOPHYS CHEM, RAHWAY, NJ 07065 USA
关键词
D O I
10.1021/jm9506736
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The design, synthesis, and biological activity of a novel series of CCK-B receptor antagonists (1) which incorporate a tetrazol-5-ylamino functionality attached to the phenyl ring of the arylurea moiety of L-365,260 are described. In these compounds, the acidity of the tetrazole was gradually modified by utilization of simple conformational constraints, and X-ray crystallographic data were obtained to support the conformational dependence of the pK(a) of the aminotetrazoles. Compounds to emerge from the present work such as 1f and 2c,d are among the highest affinity and, in the case of 1f, most selective (CCK-A/CCK-B, 37 000) antagonists so far reported for this receptor. The C-5-cyclohexyl compound 2c (L-736,380) dose-dependently inhibited gastric acid secretion in anesthetized rats (ID50, 0.064 mg/kg) and er vivo binding of [I-125]CCK-8S in BKTO mice brain membranes (ED(50), 1.7 mg/kg) and is one of the most potent acidic CCK-B receptor antagonists yet described.
引用
收藏
页码:842 / 849
页数:8
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