Inhaled long acting β2-adrenoceptor agonists (LABA) which act as bronchodilators and the oral anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor roflumilast are both approved therapies for chronic obstructive pulmonary disease (COPD). Here we describe the activity of a novel, inhaled, bifunctional, small molecule (R)-6-((3-((4-(5-((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pent-1-yn-1-yl)phenyl)carbamoyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (GS-5759) which has specific β2 agonist and PDE4 inhibitory activity. GS-5759 demonstrated potent and full agonist activity at β2-adrenoceptors (EC50 = 8 ± 4 nM) and is a potent inhibitor of the PDE4 enzyme (IC50 = 5 ± 3 nM). In cell assays, GS-5759 inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNFα) production in human peripheral mononuclear cells (PBMC) with an IC50 = 0.3 nM (C.I. 0.1-0.6) and in human neutrophils fMLP-induced super oxide anion production with an IC50 = 3 nM (C.I. 1-8). Addition of the β2 antagonist ICI 118551 shifted the IC50 in these cell assays to 4 and 38 nM respectively, demonstrating the contribution of both β2 agonist and PDE4 inhibitory activity to GS-5759. GS-5759 was also a potent inhibitor of profibrotic and pro-inflammatory mediator release from human lung fibroblasts. GS-5759 relaxed guinea pig airway smooth muscle strips pre-contracted with carbachol in a concentration-dependent manner with an EC50 = 0.5 µM (C.I. 0.2-2) and had slow dissociation kinetics with an Off T½ >720 min at an EC80 concentration of 3 µM. GS-5759 is a novel bifunctional molecule with both potent β2 agonist and PDE4 inhibitor activity which could provide inhaled bronchodilator and anti-inflammatory therapy for COPD.
- beta-adrenergic receptors
- chronic obstructive pulmonary disease
- respiratory pharmacology
- The American Society for Pharmacology and Experimental Therapeutics