Pharmacology and Clinical Activity of Toreforant, A Histamine H4 Receptor Antagonist

Toreforant is a potent and selective histamine H4 receptor (H4R) antagonist with a Ki at the human receptor of 8.4 ± 2.2 nM and excellent selectivity over other receptors including the other histamine receptors. The compound acts as an antagonist in all species tested and inhibits histamine-induced eosinophil shape change in vitro. Toreforant was anti-inflammatory in mouse models of asthma and arthritis. However, it was not able to inhibit histamine-induced scratching in mice or block neuropathic pain in rats. The lack of effect in these models may be related to low exposure levels in the central nervous system. Preclinical toxicity studies of up to 6 months in rats and 9 months in monkeys indicated an excellent safety profile with the exception of QT prolongation seen in vivo due to inhibition of the human ether-à-go-go-related gene (hERG) channel. Toreforant was studied in phase 1 human clinical studies to assess safety, pharmacokinetics and pharmacodynamics. The compound was well-tolerated at all doses tested and no safety issues were noted in the phase 1 studies with the exception of QT prolongation observed at the highest dose. Toreforant exhibited good pharmacokinetics upon oral dosing with a plasma half-life consistent with once a day dosing. In addition, dose-dependent inhibition of histamine-induced eosinophil shape change was detected suggesting that the H4R was inhibited in vivo.