Abstract
Inhaled long-acting β2-adrenoceptor agonists (LABA) that 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 [confidence interval (CI) 0.1–0.6] and in human neutrophils formyl-methionyl-leucyl-phenylalanine (fMLP)-induced super oxide anion production with an IC50 = 3 nM (CI 0.8–8). The 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 proinflammatory mediator release from human lung fibroblasts. GS-5759 relaxed guinea pig airway smooth muscle strips precontracted with carbachol in a concentration-dependent manner with an EC50 = 0.5 µM (CI 0.2–2) and had slow dissociation kinetics with an Off T1/2 > 720 minutes at an EC80 concentration of 3 µM. GS-5759 is a novel bifunctional molecule with both potent β2 agonist and PDE4 inhibitor activity that could provide inhaled bronchodilator and anti-inflammatory therapy for COPD.
Footnotes
- Received November 5, 2013.
- Accepted February 7, 2014.
↵1 Current affiliation: Merck Research Laboratories, Boston, Massachusetts.
This study was funded by Gilead Sciences, Inc.
Portions of this work were presented at the following meetings: Tannheimer SL, Wright CW, and Salmon M (2012) GS-5759, a novel bi-functional phosphodiesterase 4 inhibitor and long-acting β2-adrenoceptor agonist has anti-inflammatory and anti-remodeling activity in human lung fibroblasts; Sorensen EA, Tannheimer SL, Haran AC, Wright CW, and Salmon M (2012) GS-5759, a novel bi-functional phosphodiesterase 4 inhibitor and long-acting β2-adrenoceptor agonist, has potent anti-inflammatory activity in human monocytes and neutrophils; and Cui Z-H, Gentzler TT, and Salmon M (2012) GS-5759, a novel bi-functional phosphodiesterase 4 inhibitor and long-acting β2-adrenoceptor agonist, in vitro pharmacology on guinea pig tracheal smooth muscle strips. American Thoracic Society International Conference; 18–23 May 2012; San Francisco, CA; and Kim M, Patel L, Purvis LJ, Cui Z, Gentzler T, Salmon M, Sorensen R, Tannheimer S, and Phillps G (2012) Dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatment of respiratory disease: (III) Discovery of GS-5759. 244th American Chemical Society National Meeting & Exposition; 19-23 Aug 2012; Philadelphia, PA.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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