title: The in vitro pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long acting β2-adrenoceptor agonist.
abstract: Inhaled long-acting β(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 (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 β(2) agonist and PDE4 inhibitory activity. GS-5759 demonstrated potent and full agonist activity at β(2) adrenoceptors (EC(50) = 8 ± 4 nM) and is a potent inhibitor of the PDE4 enzyme (IC(50) = 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 IC(50) = 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) = 3 nM (CI 0.8-8). The addition of the β(2) antagonist ICI 118551 shifted the IC(50) in these cell assays to 4 and 38 nM, respectively, demonstrating the contribution of both β(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 concentration-dependent manner with an EC(50) = 0.5 µM (CI 0.2-2) and had slow dissociation kinetics with an Off T(1/2) > 720 minutes at an EC(80) concentration of 3 µM. GS-5759 is a novel bifunctional molecule with both potent β(2) agonist and PDE4 inhibitor activity that could provide inhaled bronchodilator and anti-inflammatory therapy for COPD.
authors: Oncology/Inflammation Research (S.L.T., E.A.S., Z-H.C., C.D.W., M.S.), Medicinal Chemistry (M.K., L.P., W.R.B., G.B.P.), Gilead Sciences Inc., Seattle, Washington.
authors: Stacey L
authors: SL
authors: Tannheimer
authors: Eric A
authors: EA
authors: Sorensen
authors: Zhi-Hua
authors: ZH
authors: Cui
authors: Musong
authors: M
authors: Kim
authors: Leena
authors: L
authors: Patel
authors: William R
authors: WR
authors: Baker
authors: Gary B
authors: GB
authors: Phillips
authors: Clifford D
authors: CD
authors: Wright
authors: Michael
authors: M
authors: Salmon
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018929:Cell Culture Techniques; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000276:immunology; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012137:Respiratory System / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
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; D058666:Adrenergic beta-2 Receptor Agonists; D016207:Cytokines; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; D015363:Quinolones; D013450:Sulfones