The in vitro pharmacology and non-clinical cardiovascular safety studies of a novel 5-HT 4 receptor agonist, DSP-6952

Abstract

The pharmacological activity of DSP-6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5-hydroxytryptamine (5-HT) receptor agonists. DSP-6952 had a strong affinity of Ki = 51.9 nM for 5-HT receptor, and produced contraction in the isolated guinea pig colon with EC of 271.6 nM and low intrinsic activity of 57%, similar to tegaserod and mosapride. In the development of the 5-HT 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-HT receptor antagonist, and another 5-HT receptor agonist, TD-5108 also increased heart rate. These effects are considered a class effect seen in clinically developing and marketed 5-HT 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-HT receptor agonistic activity as well as a favorable cardiovascular safety profile.

A 3‐Part Phase 1 Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DSP‐6952 in Healthy Japanese Subjects and Those With ≤3 Spontaneous Bowel Movements per Week

“…It is also noteworthy that in the present study there were no deaths, cardiovascular toxicity, or abnormal changes in vital signs or 12‐lead electrocardiography. The results of the present study are aligned with those of a preclinical study, which reported that despite a dose‐dependent increase in the heart rate of monkeys treated with DSP‐6952, blood pressure remained normal, and no abnormal electrocardiographic findings, including prolongation of QTc Bazett, were noted . In the same preclinical study DSP‐6952 did not cause coronary artery constriction in rabbits, unlike tegaserod, suggesting that the DSP‐6952 does not induce ischemic heart disease …”

“…The results of the present study are aligned with those of a preclinical study, which reported that despite a dose-dependent increase in the heart rate of monkeys treated with DSP-6952, blood pressure remained normal, and no abnormal electrocardiographic findings, including prolongation of QTc Bazett, were noted. 7 In the same preclinical study DSP-6952 did not cause coronary artery constriction in rabbits, unlike tegaserod, suggesting that the DSP-6952 does not induce ischemic heart disease. 7 Regarding the PK results, after single-dose administration in fasting conditions, the t max of DSP-6952 occurred at 0.5-1 hour after administration, and the t ½ was 7-8 hours.…”

“…7 In the same preclinical study DSP-6952 did not cause coronary artery constriction in rabbits, unlike tegaserod, suggesting that the DSP-6952 does not induce ischemic heart disease. 7 Regarding the PK results, after single-dose administration in fasting conditions, the t max of DSP-6952 occurred at 0.5-1 hour after administration, and the t ½ was 7-8 hours. The plasma concentration profile of DSP-6952 had 2 peaks at all the doses, which might have been caused by enterohepatic circulation.…”

“…DSP‐6952 is a potential gastrointestinal prokinetic agent with high affinity for 5‐HT 4 receptors that acts as a partial agonist . The chemical structure of DSP‐6952 is shown in Figure .…”

“…DSP-6952 is a potential gastrointestinal prokinetic agent with high affinity for 5-HT 4 receptors that acts as a partial agonist. 7 The chemical structure of DSP-6952 is shown in Figure 1. Unlike secretagogue laxatives, DSP-6952 is likely to induce natural bowel movements by enhancing gastrointestinal motility and colonic transit without diarrhea or abdominal pain.…”