Norman M H, Rigdon G C, Hall W R, Navas F
Division of Chemistry, Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709, USA.
J Med Chem. 1996 Mar 1;39(5):1172-88. doi: 10.1021/jm950551d.
A series of substituted (4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide derivatives was prepared and evaluated as potential atypical antipsychotic agents. The target compounds were readily prepared from their benzoyl chloride, benzoic acid, or isatoic anhydride precursors, and they were evaluated in vitro for their ability to bind to dopamine D2, serotonin 5-HT2, and serotonin 5-HT1a receptors. To assess the potential antipsychotic activity of these compounds, we investigated their ability to inhibit the apomorphine-induced climbing response in mice. Selected compounds were evaluated further to determine their side-effect potentials. Structure-activity relationships of both mono- and polysubstituted benzamides are discussed herein. While several analogues had potent in vitro and in vivo activities indicative of potential atypical antipsychotic activity, anthranilamide 77 (1192U90) ddemonstrated a superior pharmacological profile. As a result of this investigation, 1192U90 (2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)ben zamide hydrochloride) was selected for further evaluation and is currently in phase I clinical trials as a potential atypical antipsychotic agent.
制备了一系列取代的（4-（4-（1,2-苯并异噻唑-3-基）-1-哌嗪基）丁基）苯甲酰胺衍生物，并将其作为潜在的非典型抗精神病药物进行评估。目标化合物可容易地从其苯甲酰氯、苯甲酸或邻氨基苯甲酸酐前体制备，并在体外评估它们与多巴胺D2、5-羟色胺5-HT2和5-羟色胺5-HT1a受体结合的能力。为了评估这些化合物的潜在抗精神病活性，我们研究了它们抑制小鼠阿扑吗啡诱导的攀爬反应的能力。对选定的化合物进行了进一步评估，以确定其副作用潜力。本文讨论了单取代和多取代苯甲酰胺的构效关系。虽然几种类似物具有表明潜在非典型抗精神病活性的强效体外和体内活性，但邻氨基苯甲酰胺77（1192U90）表现出更优异的药理学特征。作为这项研究的结果，选择了1192U90（2-氨基-N-（4-（4-（1,2-苯并异噻唑-3-基）-1-哌嗪基）丁基）苯甲酰胺盐酸盐）进行进一步评估，目前它作为一种潜在的非典型抗精神病药物正处于I期临床试验阶段。
