PMID- 24513870
OWN - NLM
STAT- MEDLINE
DCOM- 20140514
LR  - 20141120
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
VI  - 349
IP  - 1
DP  - 2014 Apr
TI  - The in vitro pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 
      inhibitor and long acting beta2-adrenoceptor agonist.
PG  - 85-93
LID - 10.1124/jpet.113.210997 [doi]
AB  - Inhaled long-acting beta(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]aminopent-1-yn-1-yl)phenyl]carbamoylphenyl)sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide 
      (GS-5759), which has specific beta(2) agonist and PDE4 inhibitory activity. GS-5759 
      demonstrated potent and full agonist activity at beta(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 
      alpha (TNFalpha) 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 beta(2) antagonist ICI 118551 
      shifted the IC(50) in these cell assays to 4 and 38 nM, respectively, 
      demonstrating the contribution of both beta(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 microM (CI 0.2-2) and had slow 
      dissociation kinetics with an Off T(1/2) > 720 minutes at an EC(80) concentration 
      of 3 microM. GS-5759 is a novel bifunctional molecule with both potent beta(2) agonist 
      and PDE4 inhibitor activity that could provide inhaled bronchodilator and 
      anti-inflammatory therapy for COPD.
FAU - Tannheimer, Stacey L
AU  - Tannheimer SL
AD  - 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.
FAU - Sorensen, Eric A
AU  - Sorensen EA
FAU - Cui, Zhi-Hua
AU  - Cui ZH
FAU - Kim, Musong
AU  - Kim M
FAU - Patel, Leena
AU  - Patel L
FAU - Baker, William R
AU  - Baker WR
FAU - Phillips, Gary B
AU  - Phillips GB
FAU - Wright, Clifford D
AU  - Wright CD
FAU - Salmon, Michael
AU  - Salmon M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140210
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 
      (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)
RN  - 0 (Adrenergic beta-2 Receptor Agonists)
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Phosphodiesterase 4 Inhibitors)
RN  - 0 (Quinolones)
RN  - 0 (Sulfones)
SB  - IM
MH  - Adrenergic beta-2 Receptor Agonists/chemical synthesis/chemistry/*pharmacology
MH  - Animals
MH  - Cell Culture Techniques
MH  - Cytokines/antagonists & inhibitors/immunology
MH  - Fibroblasts/*drug effects/enzymology/immunology/metabolism
MH  - Guinea Pigs
MH  - Humans
MH  - Leukocytes, Mononuclear/*drug effects/enzymology/immunology/metabolism
MH  - Lipopolysaccharides/pharmacology
MH  - Male
MH  - Molecular Structure
MH  - Muscle, Smooth/*drug effects/enzymology/immunology/metabolism
MH  - Phosphodiesterase 4 Inhibitors/chemical synthesis/chemistry/*pharmacology
MH  - Pulmonary Disease, Chronic Obstructive/drug therapy
MH  - Quinolones/chemical synthesis/chemistry/*pharmacology
MH  - Respiratory System/*drug effects/enzymology/immunology/metabolism
MH  - Sulfones/chemical synthesis/chemistry/*pharmacology
MH  - Time Factors
EDAT- 2014/02/12 06:00
MHDA- 2014/05/16 06:00
CRDT- 2014/02/12 06:00
PHST- 2014/02/12 06:00 [entrez]
PHST- 2014/02/12 06:00 [pubmed]
PHST- 2014/05/16 06:00 [medline]
AID - jpet.113.210997 [pii]
AID - 10.1124/jpet.113.210997 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2014 Apr;349(1):85-93. doi: 10.1124/jpet.113.210997. Epub 
      2014 Feb 10.