TY - JOUR T1 - Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 2. Efficacy studies in allergic and pulmonary inflammation models in vivo. AU - Stenton,Grant R, AU - Mackenzie,Lloyd F, AU - Tam,Patrick, AU - Cross,Jennifer L, AU - Harwig,Curtis, AU - Raymond,Jeffrey, AU - Toews,Judy, AU - Chernoff,David, AU - MacRury,Thomas, AU - Szabo,Csaba, PY - 2012/03/22/received PY - 2012/09/14/revised PY - 2012/10/16/accepted PY - 2012/11/6/entrez PY - 2012/11/6/pubmed PY - 2013/8/24/medline SP - 1519 EP - 29 JF - British journal of pharmacology JO - Br J Pharmacol VL - 168 IS - 6 N2 - 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. EXPERIMENTAL APPROACH: 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/23121409/Characterization_of_AQX_1125_a_small_molecule_SHIP1_activator:_Part_2__Efficacy_studies_in_allergic_and_pulmonary_inflammation_models_in_vivo_ L2 - https://doi.org/10.1111/bph.12038 DB - PRIME DP - Unbound Medicine ER -