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Two biomimetic approaches have been used to synthesize analogs of the SHIP1‐activating sponge meroterpenoid pelorol (1). One approach started from the chiral pool plant natural product sclareolide, which has the same absolute configuration as pelorol. The second approach utilized an enantioselective polyene cyclization to efficiently access both absolute configurations of the pelorol meroterpenoid skeleton and to prepare A‐ring functionalized compounds. Selected analogs have been evaluated for water solubility and biological activity. It was found that the undesirable catechol and ester functionalities in 1 could be removed to give MN100 (3), without a decrease in SHIP1‐activating ability. A further refinement led to the resorcinol analog 18, which is the most effective SHIP1‐activating pelorol analog made to date. The HCl salt of ent‐28, a C‐3 amino analog of 18, is about 500,000‐fold more soluble in water than MN100 (3). (±)‐28·HCl activates SHIP1 in vitro, inhibits Akt phosphorylation in stimulated MOLT‐4 (SHIP+) cells, and is active in a dose‐dependent manner in a mouse model of inflammation when administered by oral gavage (ED50 ≈ 0.1 mg/kg). Pelorol analogs ent‐28 or (±)‐28 are promising chemical tools for further preclinical in vivo evaluation of the potential of SHIP1 activators as therapeutics for treating hematopoietic diseases involving aberrant activation of PI3K cell signaling.

BACKGROUND: The guidelines to conduct and interpret conventional pulmonary function (PFT) tests are frequently reviewed and updated. However, the quality assurance and quality control (QA/QC) guidelines for respiratory oscillometry testing remain limited. QA/QC guidelines are essential for oscillometry to be used as a diagnostic pulmonary function test (PFT) in a clinical setting. METHODS: We developed a QA/QC protocol shortly after oscillometry was introduced in our laboratory as part of a clinical study. The first clinical study began after the research personnel completed 3 h of combined didactic and hands-on training and establishment of a standard operating protocol (SOP) for oscillometry testing. All oscillometry tests were conducted using the initial SOP protocol from October 17, 2017, to April 6, 2018. At this time, the first QA/QC audit took place, followed by revisions to the SOP, the addition of a QA/QC checklist, and the development of a 12-h training program. A second audit of oscillometry tests was conducted from April 9, 2018, to June 30, 2019. Both audits were completed by a registered cardiopulmonary technologist from the Toronto General Pulmonary Function Lab. RESULTS: The first audit evaluated 197 paired oscillometry-PFT tests and found 10 tests (5.08%) to be invalid, with a coefficient of variation > 15%. The second audit examined 1,930 paired oscillometry-PFT tests; only 3 tests (0.16%) were unacceptable, with a coefficient of variation > 15%. Improvement in QA/QC was significantly better compared to the first audit (P < .001). CONCLUSIONS: Although oscillometry requires minimal subject cooperation, application of the principles that govern the conduct and application of a PFT are important for ensuring that oscillometry testing is performed according to acceptability and reproducibility. Specifically, the inclusion of a SOP, a proper training program, a QA/QC checklist, and regular audits with feedback are vital to ensure that oscillometry is conducted accurately and precisely.

BACKGROUNDThe SH2-containing inositol-5′-phosphatase 1 (SHIP1) metabolizes PI(3,4,5)P3 to PI(3,4)P2. SHIP1-deficient mice exhibit progressive inflammation. Pharmacological activation of SHIP1 is emerging as a potential therapy for pulmonary inflammatory diseases. Here we characterize the efficacy of AQX-1125, a small-molecule SHIP1 activator currently in clinical development. EXPERIMENTAL APPROACHThe effects of AQX-1125 were tested in several in vitro assays: on enzyme catalytic activity utilizing recombinant human SHIP1, on Akt phosphorylation in SHIP1-proficient and SHIP1-deficient cell lines, on cytokine release in murine splenocytes, on human leukocyte chemotaxis using modified Boyden chambers and on b-hexosaminidase release from murine mast cells. In addition, pharmacokinetic and drug distribution studies were performed in rats and dogs. RESULTSAQX-1125 increased the catalytic activity of human recombinant SHIP1, an effect, which was absent after deletion of the C2 region. AQX-1125 inhibited Akt phosphorylation in SHIP1-proficient but not in SHIP1-deficient cells, reduced cytokine production in splenocytes, inhibited the activation of mast cells and inhibited human leukocyte chemotaxis. In vivo, AQX-1125 exhibited >80% oral bioavailability and >5 h terminal half-life. CONCLUSIONSConsistent with the role of SHIP1 in cell activation and chemotaxis, the SHIP1 activator AQX-1125 inhibits Akt phosphorylation, inflammatory mediator production and leukocyte chemotaxis in vitro. The in vitro effects and the pharmacokinetic properties of the compound make it a suitable candidate for in vivo testing in various models of inflammation.