Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension
Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension
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DOI：
10.1021/acs.jmedchem.5b00698
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发表时间：
2015-09-24
影响因子：
7.3
通讯作者：
Clozel, Martine
中科院分区：
文献类型：
--
作者：
Asaki, Tetsuo;Kuwano, Keiichi;Clozel, Martine
前列环素通过激活前列环素受体来控制心血管功能。前列环素产生减少会导致多种心血管疾病。然而，前列环素及其类似物的临床使用因其化学和代谢不稳定而变得复杂。药物化学项目寻找不受这些限制的新型非前列腺素类前列环素受体激动剂。合成了具有二苯基吡嗪结构核心的化合物。通过线性侧链的修饰优化了代谢稳定性和激动剂效力。化合物 12b（MRE-269、ACT-333679）被鉴定为有效且高度选择性的前列环素受体激动剂。用 N-酰基磺酰胺基团取代末端羧基产生母体化合物 26a（selexipag，NS-304，ACT-293987），其具有口服活性并提供 12b 的持续血浆暴露。化合物 26a 被开发用于治疗肺动脉高压，并在 3 期事件驱动的临床试验中显示可降低复合发病率/死亡率终点的风险。
Prostacyclin controls cardiovascular function via activation of the prostacyclin receptor. Decreased prostacyclin production occurs in several cardiovascular diseases. However, the clinical use of prostacyclin and its analogues is complicated by their chemical and metabolic instability. A medicinal chemistry program searched for novel nonprostanoid prostacyclin receptor agonists not subject to these limitations. A compound with a diphenylpyrazine structural core was synthesized. Metabolic stability and agonist potency were optimized through modification of the linear side chain. Compound 12b (MRE-269, ACT-333679) was identified as a potent and highly selective prostacyclin receptor agonist. Replacement of the terminal carboxyl group with an N-acylsulfonamide group yielded parent compound 26a (selexipag, NS-304, ACT-293987), which is orally active and provides sustained plasma exposure of 12b. Compound 26a was developed for the treatment of pulmonary arterial hypertension and shown to reduce the risk of the composite morbidity/mortality end point in a phase 3 event-driven clinical trial.