METHODS FOR DRUG DISCOVERY - DEVELOPMENT OF POTENT, SELECTIVE, ORALLY EFFECTIVE CHOLECYSTOKININ ANTAGONISTS
METHODS FOR DRUG DISCOVERY - DEVELOPMENT OF POTENT, SELECTIVE, ORALLY EFFECTIVE CHOLECYSTOKININ ANTAGONISTS
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DOI：
10.1021/jm00120a002
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发表时间：
1988-12-01
影响因子：
7.3
通讯作者：
HIRSHFIELD, J
中科院分区：
文献类型：
--
作者：
EVANS, BE;RITTLE, KE;HIRSHFIELD, J
描述了肽激素胆囊收缩素（CCK）的拮抗剂3-（酰氨基）-5-苯基-2H-1，4-苯并二氮杂。这些化合物是通过对已知抗焦虑苯二氮卓类药物进行合理修饰而开发的，提供了对外周（CCK-A）受体具有选择性的高效、口服有效的配体，其结合亲和力接近或等于天然配体CCK-8的结合亲和力。CCK-A受体一方面和中枢神经系统（CCK-B），胃泌素，和中央苯二氮卓类受体另一方面之间的区别是通过使用新化合物的结构-活性曲线证明。详细的结合，这些代理商的CCK-A受体进行检查，并讨论了这些化合物的开发方法，在其相关的药物发现的一般问题。
3-(Acylamino)-5-phenyl-2H-l, 4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described. Developed by reasoned modificationof the known anxiolytic benzodiazepines, these compounds provide highly potent, orally effective ligands selective for peripheral (CCK-A) receptors, with binding affinities approaching or equaling that of the natural ligand CCK-8. The distinction between CCK-A receptors on the one hand and CNS (CCK-B), gastrin, and central benzodiazepine receptors on the other is demonstrated by using the structure-activity profiles of the new compounds. Details of the binding of these agents to CCK-A receptors are examined, and the method of development of these compounds isdiscussed in terms of its relevance to the general problem of drug discovery.