title: Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 2. Efficacy studies in allergic and pulmonary inflammation models in vivo.
abstract: BACKGROUND
  The efficacy of AQX-1125, a small-molecule SH2-containing inositol-5'-phosphatase 1 (SHIP1) activator and clinical development candidate, is investigated in rodent models of inflammation.
  
  
  METHODS
  AQX-1125 was administered orally in a mouse model of passive cutaneous anaphylaxis (PCA) and a number of rodent models of respiratory inflammation including: cigarette smoke, LPS and ovalbumin (OVA)-mediated airway inflammation. SHIP1 dependency of the AQX-1125 mechanism of action was investigated by comparing the efficacy in wild-type and SHIP1-deficient mice subjected to an intrapulmonary LPS challenge.
  
  
  RESULTS
  AQX-1125 exerted anti-inflammatory effects in all of the models studied. AQX-1125 decreased the PCA response at all doses tested. Using bronchoalveolar lavage (BAL) cell counts as an end point, oral or aerosolized AQX-1125 dose dependently decreased the LPS-mediated pulmonary neutrophilic infiltration at 3-30 mg kg⁻¹ and 0.15-15 μg kg⁻¹ respectively. AQX-1125 suppressed the OVA-mediated airway inflammation at 0.1-10 mg kg⁻¹. In the smoke-induced airway inflammation model, AQX-1125 was tested at 30 mg kg⁻¹ and significantly reduced the neutrophil infiltration of the BAL fluid. AQX-1125 (10 mg kg⁻¹) decreased LPS-induced pulmonary neutrophilia in wild-type mice but not in SHIP1-deficient mice.
  
  
  CONCLUSIONS
  The SHIP1 activator, AQX-1125, suppresses leukocyte accumulation and inflammatory mediator release in rodent models of pulmonary inflammation and allergy. As shown in the mouse model of LPS-induced lung inflammation, the efficacy of the compound is dependent on the presence of SHIP1. Pharmacological SHIP1 activation may have clinical potential for the treatment of pulmonary inflammatory diseases.
authors.affiliation: Aquinox Pharmaceuticals Inc., Richmond, BC, Canada. gstenton@aqxpharma.com
authors.forename: Grant R
authors.initials: GR
authors.lastname: Stenton
authors.forename: Lloyd F
authors.initials: LF
authors.lastname: Mackenzie
authors.forename: Patrick
authors.initials: P
authors.lastname: Tam
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Cross
authors.forename: Curtis
authors.initials: C
authors.lastname: Harwig
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Raymond
authors.forename: Judy
authors.initials: J
authors.lastname: Toews
authors.forename: David
authors.initials: D
authors.lastname: Chernoff
authors.forename: Thomas
authors.initials: T
authors.lastname: MacRury
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001249:Asthma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D003511:Cyclohexanols / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017449:Dermatitis, Allergic Contact / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D020536:Enzyme Activators / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D007189:Indans / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000072181:Inositol Polyphosphate 5-Phosphatases; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D012140:Respiratory Tract Diseases / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control
chemical_list: C582990:4-(4-(aminomethyl)-7a-methyl-1-methylideneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexan-1-ol; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003511:Cyclohexanols; D020536:Enzyme Activators; D007189:Indans; D007527:Isoenzymes; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases