新型5-HT4受体激动剂DSP-6952的体外药理学和非临床心血管安全性研究。,European Journal of Pharmacology

当前位置： X-MOL 学术 › Eur. J. Pharmacol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

新型5-HT4受体激动剂DSP-6952的体外药理学和非临床心血管安全性研究。
European Journal of Pharmacology ( IF 4.2 ) Pub Date : 2018-03-05 , DOI: 10.1016/j.ejphar.2018.02.037
Tadashi Tsubouchi ₁ , Takeshi Kunimatsu ₁ , Shinji Tsujimoto ₁ , Akihiko Kiyoshi ₁ , Yasunori Katsura ₁ , Seiko Oku ₁ , Kazuhiro Chihara ₁ , Yukiko Mine ₁ , Toru Yamada ₁ , Isao Shimizu ₁ , Kiyoko Bando ₁

Affiliation

与临床有效的胃肠道（GI）促运动型5-羟色胺4（5-HT4）受体激动剂相比，研究了一种新型化合物DSP-6952的药理活性。DSP-6952对5-HT4（b）受体具有Ki = 51.9 nM的强亲和力，并在分离的豚鼠结肠中产生收缩，EC50为271.6 nM，固有活性低至57％，类似于替加色罗和莫沙必利。在5-HT4受体激动剂的开发过程中，有意评估了心血管疾病的风险，因为据报道某些相关的动力学会导致心血管不良事件，例如心律失常或缺血。DSP-6952对人类以太相关基因（hERG）通道或豚鼠心肌细胞的影响最小，最高可达100μM。在遥测的有意识的猴子中，DSP-6952不会影响血压或最高心电图180 mg / kg的任何心电图（ECG）；但是，DSP-6952以及麻醉狗会暂时增加心率。5-HT4受体拮抗剂完全抵消了DSP-6952的正变时作用，而另一种5-HT4受体激动剂TD-5108也提高了心率。这些作用被认为是在临床上开发和销售的5-HT4受体激动剂中看到的一种类别作用，在临床应用中并未被视为关键问题。与替加色罗或舒马普坦不同，DSP-6952不会引起高达100μM的兔子冠状动脉收缩。这些结果表明，DSP-6952没有通过冠状动脉血管收缩引起的心脏缺血风险。综上所述，

"点击查看英文标题和摘要"

The in vitro pharmacology and non-clinical cardiovascular safety studies of a novel 5-HT4 receptor agonist, DSP-6952.

The pharmacological activity of DSP-6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5-hydroxytryptamine4 (5-HT4) receptor agonists. DSP-6952 had a strong affinity of Ki = 51.9 nM for 5-HT4(b) receptor, and produced contraction in the isolated guinea pig colon with EC50 of 271.6 nM and low intrinsic activity of 57%, similar to tegaserod and mosapride. In the development of the 5-HT4 receptor agonists, cardiovascular risk was deliberately evaluated, because some related prokinetics were reported to cause with cardiovascular adverse events, such as ventricular arrhythmias or ischemia. DSP-6952 showed minimal effects up to 100 μM in human ether-a-go-go-related gene (hERG) channels or guinea pig cardiomyocytes. In telemetered conscious monkeys, DSP-6952 did not affect blood pressure or any electrocardiogram (ECG) up to 180 mg/kg, p.o.; however, DSP-6952 transiently increased heart rate, as well as in anesthetized dogs. The positive chronotropic effects of DSP-6952 were completely antagonized by a 5-HT4 receptor antagonist, and another 5-HT4 receptor agonist, TD-5108 also increased heart rate. These effects are considered a class effect seen in clinically developing and marketed 5-HT4 receptor agonists, and have not been regarded as a critical issue in clinical use. DSP-6952 did not induce contraction in the rabbit coronary artery up to 100 μM, which differed from tegaserod or sumatriptan. These results show that DSP-6952 does not have cardiac ischemic risk via coronary vasoconstriction. In conclusion, DSP-6952 is a promising GI prokinetic compound with partial 5-HT4 receptor agonistic activity as well as a favorable cardiovascular safety profile.

更新日期：2019-11-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南