The in vivo efficacy and side effect pharmacology of GS ‐5759, a novel bifunctional phosphodiesterase 4 inhibitor and long‐acting β₂‐adrenoceptor agonist in preclinical animal species

摘要

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 ( PDE 4) 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 ED ₅₀ ≤ 10 μ g/kg. GS ‐5759 was also a potent bronchodilator with an ED ₅₀ of 0.09 μ g/kg in guinea pigs and 3.4 μ g/kg in dogs after methylcholine ( MC h) 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 MC h and LPS challenge models, with an ED ₅₀ = 70 μ g/kg for bronchodilation and ED ₅₀ = 4.9 μ g/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 ED ₅₀ 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. e00046.