GSK1004723, a novel histamine H1/H3 receptor antagonist exhibiting slow H1 dissociation kinetics

Robert Slack, Christopher Browning, David Hall, Malcolm Begg, Kenneth Clark. GlaxoSmithKline, Stevenage, United Kingdom.

Many allergic rhinitis patients cite nasal congestion as their most poorly treated symptom. It has been shown that blockade of both H1 & H3 receptors is required to significantly inhibit histamine induced congestion in human subjects (Taylor-Clark et al., 2005). GSK1004723 is a novel intranasal dual histamine H1/H3 receptor antagonist with high affinity for both receptors & a long duration of action (Clark et al., 2009). In this report (funded by GSK) we have investigated the binding kinetics of GSK1004723 at the H1 receptor.

Radioligand binding experiments were performed by filtration with [3H]-mepyramine and membrane fragments generated from CHO cells recombinantly expressing the human H1 receptor (non-specific binding defined by 10μM azelastine). Competition binding curves for GSK1004723 & azelastine were obtained over a 24h time course to estimate when equilibrium was achieved. In addition, the effect of different concentrations of GSK1004723 & azelastine on radioligand association over time was measured to determine dissociation rate constants (koff) by the method of Motulsky & Mahan (1984). GSK1004723 reached equilibrium between 6 & 24h with a pKi of 10.04±0.09. Azelastine reached equilibrium between 3 & 6h with a pKi of 9.32±0.10. The koff for GSK1004723 (0.002±0.001 min-1) was significantly slower than that for azelastine (0.009±0.001 min-1) (p<0.0001, Student’s t-test). These koff values indicate that binding equilibrium would be achieved at ∼3 & ∼15h for azelastine & GSK1004723 respectively, which is consistent with the competition time course experiments. Data shown are mean±s.e.m with n≥3.

In conclusion, GSK1004723 has ∼5-fold higher affinity and ∼5-fold lower dissociation rate constant at the H1 receptor than the selective H1 receptor antagonist, azelastine. These data are consistent with the long duration of action exhibited by GSK1004723 pre-clinically (Clark et al., 2009) and with its potential for once a day clinical dosing.

Clark et al., (2009), Allergy, 64 (S90), 129.
Motulsky & Mahan, (1984) Mol. Pharmacol. 25, 1–9.
Taylor-Clark et al., (2005) Br. J. Pharmacol. 144, (6) 867-874.