title: Effects of Urotensin II Receptor Antagonist, GSK1440115, in Asthma.
abstract: BACKGROUND
  Urotensin II (U-II) is highly expressed in the human lung and has been implicated in regulating respiratory physiology in preclinical studies. Our objective was to test antagonism of the urotensin (UT) receptor by GSK1440115, a novel, competitive, and selective inhibitor of the UT receptor, as a therapeutic strategy for the treatment of asthma.
  
  
  METHODS
  Safety, tolerability, and pharmacokinetics (PK) of single doses of GSK1440115 (1-750 mg) were assessed in a Phase I, placebo controlled study in 70 healthy subjects. In a Phase Ib study, 12 asthmatic patients were randomized into a two-period, single-blind crossover study and treated with single doses of 750 mg GSK1440115 or placebo and given a methacholine challenge.
  
  
  RESULTS
  Administration of GSK1440115 was safe and well-tolerated in healthy subjects and asthmatic patients. In both studies, there was a high degree of variability in the observed PK following oral dosing with GSK1440115 at all doses. There was a marked food effect in healthy subjects at the 50 mg dose. In the presence of food at the 750 mg dose, the time to maximal concentration was between 2 and 6 h and the terminal half-life was short at approximately 2 h. All asthmatic patients maintained greater than the predicted concentration levels necessary to achieve predicted 96% receptor occupancy for ≥3 h (between 4 and 7 h post-dose). There were no apparent trends or relationships between the systemic plasma exposure of GSK1440115 and pharmacodynamic endpoints, PC20 after methacholine challenge and FEV1, in asthmatics.
  
  
  CONCLUSIONS
  While GSK1440115 was safe and well-tolerated, it did not induce bronchodilation in asthmatics, or protect against methacholine-induced bronchospasm, suggesting that acute UT antagonism is not likely to provide benefit as an acute bronchodilator in this patient population.
authors: Virtual Proof of Concept Discovery Performance Unit GlaxoSmithKline, King of Prussia, PA, USA.
authors: Alison
authors: A
authors: Portnoy
authors: Sanjay
authors: S
authors: Kumar
authors: David J
authors: DJ
authors: Behm
authors: Kelly M
authors: KM
authors: Mahar
authors: Robert B
authors: RB
authors: Noble
authors: John P
authors: JP
authors: Throup
authors: Steven F
authors: SF
authors: Russ
keywords: asthma; receptor antagonist; urotensin II
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