Table 2.

Comparison of novel 5-HT₄ agonists

	Prucalopride	Velusetrag	ATI-7505
Chemistry	Benzofuran carboxamide	Quinolinone carboxamide	Benzamide
Selectivity and affinity for 5-HT4 receptor	Highly selective, high-affinity; weak affinity for human D4 and Σ1, and mouse 5-HT3 receptors at concentrations exceeding the Ki for 5-HT4 receptors by 290-fold	High affinity and selectivity for h5-HT4c over other biogenic amine receptors; >500-fold selective over other 5-HT receptors (including h5-HT2B, h5-HT3A)	Specific 5-HT4 full agonist activity in the GI tract, but a partial agonist activity in the heart
Metabolism	Limited hepatic, not CYP 3A4	CYP 3A4	Hydrolytic esterase, not CYP 3A4
Pharmacodynamic efficacy in humans	Accelerated colonic transit in health and chronic constipation	Accelerated colonic transit in health in dose-related fashion	Accelerated colonic transit in health
Clinical trial efficacy	Phase II and III portfolio in chronic constipation	Phase IIBPhaseIB	Phase IB
Open label effectiveness	Open label experience of ~ 1000 cumulative patient-years	–	–
Arrhythmogenicity	No arrhythmic activity in human atrial cells; inhibited hERG channel only at μmol/l concentration (IC50~4.9 10−6 mol/l); no clinically relevant cardiac AEs in clinical trials of > 4000 humans	At 3 μmol/l, no effect on hERG channel current; safety ratio versus cisapride > 1000-fold; no effect on QT in health or 400 patients with constipation	At 100 μmol/l, no effect on hERG channel; affinity ratio between IKr and 5-HT4 receptors of > 1000-fold.
Cardiovascular safety including elderly	Healthy subjects 'thorough' QTc study; safety in elderly cohort 80% on CV drugs	Healthy subjects 'thorough' QTc study; transient increase in heart rate not different from placebo	Healthy subjects 'thorough' QTc study;
Commonest AEs	Diarrhoea, nausea,headache	Diarrhoea, nausea, headacheDiarrhoea,headache	Diarrhoea, nausea,headache
Approval status	EMEA	–	–

EMEA, European Medicines Agency; hERG, human ether-à-go-go-related gene.