胆囊收缩素B受体拮抗剂酸度的可控修饰：N-（1,4-苯并二氮杂卓-3-基）-N'-[3-（四唑-5-基氨基）苯基]脲

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

作者信息

Castro J L, Ball R G, Broughton H B, Russell M G, Rathbone D, Watt A P, Baker R, Chapman K L, Fletcher A E, Patel S, Smith A J, Marshall G R, Ryecroft W, Matassa V G

机构信息

Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK.

出版信息

J Med Chem. 1996 Feb 16;39(4):842-9. doi: 10.1021/jm9506736.

DOI:10.1021/jm9506736

PMID:8632408

Abstract

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 depenence 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 (ID(50), 0.064 mg/kg) and ex vivo binding of [(125)I]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.

摘要

本文描述了一系列新型CCK - B受体拮抗剂（1）的设计、合成及生物活性。这些拮抗剂在L - 365,260的芳基脲部分的苯环上引入了一个连接有四唑-5-基氨基官能团。在这些化合物中，通过简单的构象限制逐步改变四唑的酸度，并获得X射线晶体学数据以支持氨基四唑pK(a)的构象依赖性。从目前的研究中得到的化合物，如1f和2c、d，是迄今为止报道的对该受体具有最高亲和力的拮抗剂，就1f而言，也是选择性最高的（CCK - A/CCK - B，37000）。C(5)-环己基化合物2c（L - 736,380）在麻醉大鼠中剂量依赖性地抑制胃酸分泌（ID(50)，0.064 mg/kg），并在BKTO小鼠脑膜中对[(125)I]CCK - 8S的体外结合具有抑制作用（ED(50)，1.7 mg/kg），是迄今所描述的最有效的酸性CCK - B受体拮抗剂之一。