The In Vitro Pharmacology of GS-5759, A Novel Bifunctional Phosphodiesterase 4 Inhibitor and Long Acting β₂-Adrenoceptor Agonist

Abstract

Inhaled long-acting b 2 -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 (, which has specific b 2 agonist and PDE4 inhibitory activity. GS-5759 demonstrated potent and full agonist activity at b 2 adrenoceptors (EC 50 5 8 6 4 nM) and is a potent inhibitor of the PDE4 enzyme (IC 50 5 5 6 3 nM). In cell assays, GS-5759 inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor a (TNFa) production in human peripheral mononuclear cells (PBMC) with an IC 50 5 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 IC 50 5 3 nM . The addition of the b 2 antagonist ICI 118551 shifted the IC 50 in these cell assays to 4 and 38 nM, respectively, demonstrating the contribution of both b 2 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 concentrationdependent manner with an EC 50 5 0.5 mM (CI 0.2-2) and had slow dissociation kinetics with an Off T 1/2 . 720 minutes at an EC 80 concentration of 3 mM. GS-5759 is a novel bifunctional molecule with both potent b 2 agonist and PDE4 inhibitor activity that could provide inhaled bronchodilator and anti-inflammatory therapy for COPD.

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

“…GS-5759 is a novel bifunctional PDE4 inhibitor/LABA that displays PDE4 inhibition and b 2 -agonism comparable to roflumilast and indacaterol, respectively [68]. More recently, a series of molecules that combine the anti-inflammatory PDE4 inhibitor roflumilast with the LABA salmeterol [68] have been described that is another potential example of a new drug class that combine anti-inflammatory and bronchodilator actions in a single molecule, although to date, there are very limited biological data on these molecules.…”

“…More recently, a series of molecules that combine the anti-inflammatory PDE4 inhibitor roflumilast with the LABA salmeterol [68] have been described that is another potential example of a new drug class that combine anti-inflammatory and bronchodilator actions in a single molecule, although to date, there are very limited biological data on these molecules. A potential advantage of these compounds is that both b 2 -agonists and PDE4 inhibitors rely on modulation of the second messenger cAMP to elicit their effects, and it is possible that the combination could provide additive or synergistic anti-inflammatory activity in the lung [69].…”

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β2-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase–Knockout Mice

“…PDE4s are the major isozymes highly expressed in immune cells, airway epithelial cells, and smooth muscle cells (17). The antiinflammatory effects of combining a b 2 AR with a PDE4 inhibitor were promising enough that a new chemical entity (GS-5759) for possible use in obstructive airway diseases was created by Gilead Sciences by covalently binding the b 2 AR agonists, indacaterol and carmoterol, to a potent PDE4 inhibitor, GSK256066 (21,45). In our studies, to more rigorously test whether the results that we observed were due to the "amplified" b 2 AR-cAMP resulting from coadministration of a PDE4 inhibitor, we tested four different combinations of a PDE4 inhibitor and a b 2 AR agonist (rolipram or roflumilast in combination with either formoterol or salmeterol), and compared the results to administration of the b 2 AR agonist alone ( Figures 1A and 1B).…”

Phosphodiesterase 4 inhibitors for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs

“…There have been attempts to increase tolerability and reduce adverse effects by using an inhaled mode of delivery. Also, attempts have been made to increase medication efficacy by combining PDE4Is with other drugs with dual antiinflammatory or bronchodilatory effects such as PDE3I/ PDE4I, PDE4I/PDE5I, PDE4I/PDE1I, muscarinic antagonists/PDE4I and b2 adrenoreceptor agonist/PDE4I [42,[48][49][50][51]. Recently, hybrid molecules combining salmeterol with two different PDE4Is, roflumilast and phthalazinone, and formoterol with the PDE4I, phthalazinone, have been developed [52,53].…”

“…Recently, hybrid molecules combining salmeterol with two different PDE4Is, roflumilast and phthalazinone, and formoterol with the PDE4I, phthalazinone, have been developed [52,53]. Table 2 summarizes the information known about functionality of developing drugs in preclinical phase [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64].…”