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GS-5759, a Bifunctional β2-Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells.

GS-5759, a Bifunctional β2-Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells.
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Joshi T, Yan D, Hamed O, Tannheimer SL, Phillips GB, Wright CD, Kim M, Salmon M, Newton R, Giembycz MA,


Joshi T, Yan D, Hamed O, Tannheimer SL, Phillips GB, Wright CD, Kim M, Salmon M, Newton R, Giembycz MA, (click to view)

Joshi T, Yan D, Hamed O, Tannheimer SL, Phillips GB, Wright CD, Kim M, Salmon M, Newton R, Giembycz MA,

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The Journal of pharmacology and experimental therapeutics 2016 12 07() pii jpet.116.237743
Abstract

GS-5759 is a bifunctional ligand composed of a quinolinone-containing pharmacophore (β2A) found in several β2-adrenoceptor agonists, including indacaterol, linked covalently to a phosphodiesterase 4 (PDE4) inhibitor related to GSK 256066 by a pent-1-yn-1-ylbenzene spacer. GS-5759 had similar affinity for PDE4B1 and the native β2-adrenoceptor expressed on BEAS-2B human airway epithelial cells. However, compared to the monofunctional parent compound, β2A, the KA of GS-5759 for the β2-adrenoceptor was 35-fold lower. Schild analysis determined that the affinities of the β-adrenoceptor antagonists, ICI 118551 and propranolol, were agonist-dependent being significantly lower with GS-5759 than with β2A. Collectively, these data can be explained by "forced proximity", bivalent binding where the pharmacophore in GS-5759 responsible for PDE4 inhibition also interacts with a non-allosteric domain within the β2-adrenoceptor that enhances the affinity of β2A for the orthosteric site. Microarray analyses revealed that GS-5759 increased the expression of >3500 genes in BEAS-2B cells after 2h exposure that were highly rank order correlated with gene expression changes produced by indacaterol and GSK 256066 in combination (Ind/GSK). Moreover, the line of regression began close to the origin with a slope of 0.89 indicating that the magnitude of most gene expression changes produced by Ind/GSK was quantitatively replicated by GS-5759. Thus, GS-5759 is a novel compound exhibiting dual β2-adrenoceptor agonism and PDE4 inhibition with potential to interact on target tissues in a synergistic manner. Such polypharmacological behaviour may be particularly effective in chronic obstructive pulmonary disease and other complex disorders where multiple processes interact to promote disease pathogenesis and progression.

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