title: The in vivo efficacy and side effect pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long-acting β 2-adrenoceptor agonist in preclinical animal species.
abstract: Bronchodilators are a central therapy for symptom relief in respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, with inhaled β 2-adrenoceptor agonists and anticholinergics being the primary treatments available. The present studies evaluated the in vivo pharmacology of (R)-6-[[3-[[4-[5-[[2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]pent-1-ynyl]phenyl]carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GS-5759), a novel bifunctional compound with both phosphodiesterase 4 (PDE4) inhibitor and long-acting β 2-adrenoceptor agonist (LABA) activity, which has been optimized for inhalation delivery. GS-5759 dose-dependently inhibited pulmonary neutrophilia in a lipopolysaccharide (LPS) aerosol challenge model of inflammation in rats with an ED50 ≤ 10 μg/kg. GS-5759 was also a potent bronchodilator with an ED50 of 0.09 μg/kg in guinea pigs and 3.4 μg/kg in dogs after methylcholine (MCh) and ragweed challenges respectively. In cynomolgus monkeys, GS-5759 was dosed as a fine-particle dry powder and was efficacious in the same dose range in both MCh and LPS challenge models, with an ED50 = 70 μg/kg for bronchodilation and ED50 = 4.9 μg/kg for inhibition of LPS-induced pulmonary neutrophilia. In models to determine therapeutic index (T.I.), efficacy for bronchodilation was evaluated against increased heart rate and GS-5759 had a T.I. of 700 in guinea pigs and >31 in dogs. In a ferret model of emesis, no emesis was seen at doses several orders of magnitude greater than the ED50 observed in the rat LPS inflammation model. GS-5759 is a bifunctional molecule developed for the treatment of COPD, which has both bronchodilator and anti-inflammatory activity and has the potential for combination as a triple therapy with a second compound, within a single inhalation device.
authors.affiliation: Oncology/Inflammation Research, Gilead Sciences Inc. 199 East Blaine Street, Seattle, Washington, 98102 ; Merck Research Laboratories 33 Avenue Louis Pasteur, Boston, Massachusetts, 02115.
authors.forename: Michael
authors.initials: M
authors.lastname: Salmon
authors.affiliation: Oncology/Inflammation Research, Gilead Sciences Inc. 199 East Blaine Street, Seattle, Washington, 98102.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Tannheimer
authors.affiliation: Oncology/Inflammation Research, Gilead Sciences Inc. 199 East Blaine Street, Seattle, Washington, 98102.
authors.forename: Terry T
authors.initials: TT
authors.lastname: Gentzler
authors.affiliation: Oncology/Inflammation Research, Gilead Sciences Inc. 199 East Blaine Street, Seattle, Washington, 98102.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Cui
authors.affiliation: Oncology/Inflammation Research, Gilead Sciences Inc. 199 East Blaine Street, Seattle, Washington, 98102.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Sorensen
authors.affiliation: Oncology/Inflammation Research, Gilead Sciences Inc. 199 East Blaine Street, Seattle, Washington, 98102.
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Hartsough
authors.affiliation: Medicinal Chemistry, Gilead Sciences Inc. 199 East Blaine Street, Seattle, Washington, 98102.
authors.forename: Musong
authors.initials: M
authors.lastname: Kim
authors.affiliation: Medicinal Chemistry, Gilead Sciences Inc. 199 East Blaine Street, Seattle, Washington, 98102.
authors.forename: Lafe J
authors.initials: LJ
authors.lastname: Purvis
authors.affiliation: Lovelace Respiratory Research Institute 2425 Ridgecrest Drive SE, Albuquerque, New Mexico, 87108.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Barrett
authors.affiliation: Lovelace Respiratory Research Institute 2425 Ridgecrest Drive SE, Albuquerque, New Mexico, 87108.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: McDonald
authors.affiliation: Lovelace Respiratory Research Institute 2425 Ridgecrest Drive SE, Albuquerque, New Mexico, 87108.
authors.forename: Karin
authors.initials: K
authors.lastname: Rudolph
authors.affiliation: Lovelace Respiratory Research Institute 2425 Ridgecrest Drive SE, Albuquerque, New Mexico, 87108.
authors.forename: Melanie
authors.initials: M
authors.lastname: Doyle-Eisele
authors.affiliation: Lovelace Respiratory Research Institute 2425 Ridgecrest Drive SE, Albuquerque, New Mexico, 87108.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kuehl
authors.affiliation: Lovelace Respiratory Research Institute 2425 Ridgecrest Drive SE, Albuquerque, New Mexico, 87108.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Royer
authors.affiliation: Medicinal Chemistry, Gilead Sciences Inc. 199 East Blaine Street, Seattle, Washington, 98102.
authors.forename: William R
authors.initials: WR
authors.lastname: Baker
authors.affiliation: Medicinal Chemistry, Gilead Sciences Inc. 199 East Blaine Street, Seattle, Washington, 98102.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Phillips
authors.affiliation: Oncology/Inflammation Research, Gilead Sciences Inc. 199 East Blaine Street, Seattle, Washington, 98102.
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Wright
keywords: Animal model; COPD; anti-inflammatory; bronchodilator; phoshphodiestersae 4; β2-adrenoceptor agonist