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(Chest. 2003;123:371S.)
© 2003 American College of Chest Physicians

UCB 62045*

Pharmacology of a Novel, Dual-Function Anti-inflammatory Agent With Histamine Type 1 Receptor Antagonist and 5-Lipoxygenase Inhibitor Activity

William M. Selig, PhD; Lynn Bayless, MS; Lyn Libertine, BA; Joseph B. Eckman, BS; Donna M. Wypij, PhD; Bruce F. Wels, MS; Maria Eckert, BS; Michelle A. Young, MS; Jean M. Nicolas, PhD; Ralph T. Scannell, PhD and James L. Ellis, PhD

From UCB Research, Inc., Cambridge, MA.

Correspondence to: William M. Selig, PhD, Associate Director of Pharmacology, UCB Research, Inc., 840 Memorial Dr, Cambridge, MA 02139; e-mail: william.selig{at}ucb-group.com

Both histamine and the leukotrienes are thought to be pivotal mediators in asthma as well as other inflammatory or allergic pathophysiologies. Evidence suggests that the combination of leukotriene antagonists and antihistamines (zafirlukast or montelukast plus loratidine) may reduce both experimental and clinical asthma or rhinitis. We synthesized a low-molecular-weight compound, UCB 62045 (563 molecular weight) [UCB Research; Cambridge, MA], which antagonizes the histamine type 1 receptor (26 nmol/L Ki in CHO cells transfected with the human histamine type 1 receptor). UCB 62045 also inhibits 5-lipoxygenase (inhibitory concentrations producing a 50% reduction in effect of 193 nmol/L and 88 nmol/L against human recombinant 5-lipoxygenase and inhibition of A23187-induced leukotriene B4 generation in human whole blood, respectively). Orally administered UCB 62045 (2 mg/kg in 1% methylcellulose) dose-dependently inhibited both histamine-induced bronchoconstriction (0%, 98%, and 97% at 1, 3, and 6 h after dosing) and ex vivo A23187-induced leukotriene B4 generation in the guinea pig (66%, 73%, and 88% at 1, 3, and 6 h after dosing, respectively). In addition, UCB 62045 (2 mg/kg) also reduced both the histamine- and leukotriene-dependent components of allergic bronchoconstriction (ovalbumin, 0.1 mg/mL IV) in the anesthetized allergic guinea pig model (37%, 86%, and 91% at 1, 3, and 6 h after dosing, respectively). These results suggest that UCB 62045 and related molecules may prove to be clinically beneficial in the treatment of airway diseases such as asthma by providing anti-inflammatory activity through the reduced production of all leukotrienes in combination with antihistaminergic actions.





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