Evans B E, Rittle K E, Bock M G, DiPardo R M, Freidinger R M, Whitter W L, Lundell G F, Veber D F, Anderson P S, Chang R S
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
J Med Chem. 1988 Dec;31(12):2235-46. doi: 10.1021/jm00120a002.
3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described. Developed by reasoned modification of 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 is discussed in terms of its relevance to the general problem of drug discovery.
本文描述了3-（酰氨基）-5-苯基-2H-1,4-苯并二氮杂卓类化合物，它们是肽激素胆囊收缩素（CCK）的拮抗剂。通过对已知抗焦虑苯并二氮杂卓类化合物进行合理修饰而开发出的这些化合物，提供了对外周（CCK-A）受体具有高度活性、口服有效的选择性配体，其结合亲和力接近或等同于天然配体CCK-8。通过使用新化合物的构效关系图谱，证明了一方面CCK-A受体与另一方面中枢神经系统（CCK-B）、胃泌素和中枢苯并二氮杂卓受体之间的区别。研究了这些药物与CCK-A受体结合的细节，并就其与药物发现这一普遍问题的相关性讨论了这些化合物的开发方法。
