title: 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.
abstract: (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)sulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide trifluoroacetic acid (GS-5759) is a bifunctional ligand composed of a quinolinone-containing pharmacophore [β2-adrenoceptor agonist orthostere (β2A)] found in several β2-adrenoceptor agonists, including indacaterol, linked covalently to a phosphodiesterase 4 (PDE4) inhibitor related to 6-[3-(dimethylcarbamoyl)benzenesulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GSK 256066) by a pent-1-yn-1-ylbenzene spacer. GS-5759 had a similar affinity for PDE4B1 and the native β2-adrenoceptor expressed on BEAS-2B human airway epithelial cells. However, compared with the monofunctional parent compound, β2A, the KAof GS-5759 for the β2-adrenoceptor was 35-fold lower. Schild analysis determined that the affinities of the β-adrenoceptor antagonists, (2R,3R)-1-[(2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl) amino]-2-butanol (ICI 118551) and propranolol, were agonist-dependent, being significantly lower for GS-5759 than 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 nonallosteric domain within the β2-adrenoceptor that enhances the affinity of β2A for the orthosteric site. Microarray analyses revealed that, after 2-hour exposure, GS-5759 increased the expression of >3500 genes in BEAS-2B cells 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 0.88, 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 behavior may be particularly effective in chronic obstructive pulmonary disease and other complex disorders where multiple processes interact to promote disease pathogenesis and progression.
authors.affiliation: Departments of Physiology and Pharmacology (T.J., D.Y., O.H., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and Translational Medicine, Biomarkers (S.L.T.), Inflammation Research (C.D.W., M.S.), and Medicinal Chemistry (G.B.P., M.K.), Gilead Sciences Inc., Seattle, Washington.
authors.forename: Taruna
authors.initials: T
authors.lastname: Joshi
authors.affiliation: Departments of Physiology and Pharmacology (T.J., D.Y., O.H., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and Translational Medicine, Biomarkers (S.L.T.), Inflammation Research (C.D.W., M.S.), and Medicinal Chemistry (G.B.P., M.K.), Gilead Sciences Inc., Seattle, Washington.
authors.forename: Dong
authors.initials: D
authors.lastname: Yan
authors.affiliation: Departments of Physiology and Pharmacology (T.J., D.Y., O.H., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and Translational Medicine, Biomarkers (S.L.T.), Inflammation Research (C.D.W., M.S.), and Medicinal Chemistry (G.B.P., M.K.), Gilead Sciences Inc., Seattle, Washington.
authors.forename: Omar
authors.initials: O
authors.lastname: Hamed
authors.affiliation: Departments of Physiology and Pharmacology (T.J., D.Y., O.H., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and Translational Medicine, Biomarkers (S.L.T.), Inflammation Research (C.D.W., M.S.), and Medicinal Chemistry (G.B.P., M.K.), Gilead Sciences Inc., Seattle, Washington.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Tannheimer
authors.affiliation: Departments of Physiology and Pharmacology (T.J., D.Y., O.H., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and Translational Medicine, Biomarkers (S.L.T.), Inflammation Research (C.D.W., M.S.), and Medicinal Chemistry (G.B.P., M.K.), Gilead Sciences Inc., Seattle, Washington.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Phillips
authors.affiliation: Departments of Physiology and Pharmacology (T.J., D.Y., O.H., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and Translational Medicine, Biomarkers (S.L.T.), Inflammation Research (C.D.W., M.S.), and Medicinal Chemistry (G.B.P., M.K.), Gilead Sciences Inc., Seattle, Washington.
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Wright
authors.affiliation: Departments of Physiology and Pharmacology (T.J., D.Y., O.H., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and Translational Medicine, Biomarkers (S.L.T.), Inflammation Research (C.D.W., M.S.), and Medicinal Chemistry (G.B.P., M.K.), Gilead Sciences Inc., Seattle, Washington.
authors.forename: Musong
authors.initials: M
authors.lastname: Kim
authors.affiliation: Departments of Physiology and Pharmacology (T.J., D.Y., O.H., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and Translational Medicine, Biomarkers (S.L.T.), Inflammation Research (C.D.W., M.S.), and Medicinal Chemistry (G.B.P., M.K.), Gilead Sciences Inc., Seattle, Washington.
authors.forename: Michael
authors.initials: M
authors.lastname: Salmon
authors.affiliation: Departments of Physiology and Pharmacology (T.J., D.Y., O.H., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and Translational Medicine, Biomarkers (S.L.T.), Inflammation Research (C.D.W., M.S.), and Medicinal Chemistry (G.B.P., M.K.), Gilead Sciences Inc., Seattle, Washington.
authors.forename: Robert
authors.initials: R
authors.lastname: Newton
authors.affiliation: Departments of Physiology and Pharmacology (T.J., D.Y., O.H., M.A.G.) and Cell Biology and Anatomy (R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and Translational Medicine, Biomarkers (S.L.T.), Inflammation Research (C.D.W., M.S.), and Medicinal Chemistry (G.B.P., M.K.), Gilead Sciences Inc., Seattle, Washington giembycz@ucalgary.ca.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Giembycz
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000634:Aminoquinolines / Q000494:pharmacology; D002460:Cell Line; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007189:Indans / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D012137:Respiratory System / Q000473:pathology*; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C588263:6-((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; C549469:6-((3-((dimethylamino)carbonyl)phenyl)sulfonyl)-8-methyl-4-((3-methyloxyphenyl)amino)-3-quinolinecarboxamide; D058666:Adrenergic beta-2 Receptor Agonists; D000634:Aminoquinolines; D007189:Indans; D058988:Phosphodiesterase 4 Inhibitors; D015363:Quinolones; D018343:Receptors, Adrenergic, beta-2; D013450:Sulfones; C510790:indacaterol; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4