Design and synthesis of trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxadiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SB-414796):: A potent and selective dopamine D3 receptor antagonist
Design and synthesis of trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxadiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SB-414796):: A potent and selective dopamine D3 receptor antagonist
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DOI：
10.1021/jm030817d
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发表时间：
2003-11-06
影响因子：
7.3
通讯作者：
Ashby, CR
中科院分区：
文献类型：
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作者：
Macdonald, GJ;Branch, CL;Ashby, CR
在其临床剂量下，目前的抗精神病药物具有多巴胺D-2和D-3受体阻滞剂的特性。然而，目前许多药物的主要缺点是观察到的锥体外系副作用（EPS），推测是由D-2受体拮抗作用引起的。因此，选择性多巴胺D-3受体拮抗剂可以提供一种有吸引力的抗精神病治疗，没有不必要的EPS。利用先前报道的两个系列的有效的和选择性的D-3受体拮抗剂中获得的SAR信息，例如2，3，4，5-四氢-1H-3-苯并氮杂卓10和2，3-二氢-1H-异吲哚啉11，已经制备了一系列7-磺酰氧基-和7-磺酰基苯并氮杂卓。这种类型的化合物结合了高水平的D-3亲和力和选择性与D-2在大鼠中具有优异的药代动力学特征。随后对该系列进行优化，以提高对一系列受体的选择性并降低细胞色素P450抑制潜力，得到反式-3-（2-（4-（（3-（3-（5-甲基-1，2，4-恶唑基））苯基）甲酰胺基）环己基）乙基）-7-甲磺酰基-2，3，4，5-四氢-1H-3-苯并氮杂卓（58，SB-414796）。该化合物是一种有效的和选择性的多巴胺D3受体拮抗剂，具有高口服生物利用度，是大鼠中枢神经系统渗透剂。随后在大鼠中的评估显示，与黑质（A9）相比，58优先减少腹侧被盖区（A10）中多巴胺能细胞的放电，这一观察结果与非典型抗精神病药功效的预测一致。在另一项研究中，58已被证明可以阻断雄性大鼠对可卡因的条件性位置偏好（CPP）反应的表达，这表明它也可能在治疗无药物可卡因成瘾者的线索诱导复发中发挥作用。
At their clinical doses, current antipsychotic agents share the property of both dopamine D-2 and D-3 receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D-2 receptor antagonism. Consequently, a selective dopamine D-3 receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D-3 receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzazepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzazepines has been prepared. Compounds of this type combined a high level of D-3 affinity and selectivity vs D-2 with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D3 receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have a role in the treatment of cue-induced relapse in drug-free cocaine addicts.