ABSTRACT
MGAT2 (monoacylglycerol acyltransferase 2) is expected to be an attractive target for the drug treatment of obesity, diabetes, and other disease. We describe our exploration and structure-activity relationship (SAR) study of 2,3-dihydro-1H-isoindole-5-sulfonamide derivatives. In this study, we identified 29 as an orally available inhibitor of MGAT2 through optimization especially in terms of solubility. This compound exhibited moderate potency in the enzyme inhibitory assay (IC50 = 1522 nM) and significant suppression of fat absorption (57% inhibition) in mice oral lipid tolerance test.
Subject(s)
Diabetes Mellitus/drug therapy , N-Acetylglucosaminyltransferases/antagonists & inhibitors , Obesity/drug therapy , Sulfonamides/chemistry , Tetrahydroisoquinolines/chemistry , Animals , Humans , Mice , Structure-Activity RelationshipABSTRACT
A previous multi-center validation study demonstrated high transferability and reliability of reactive oxygen species (ROS) assay for photosafety evaluation. The present validation study was undertaken to verify further the applicability of different solar simulators and assay performance. In 7 participating laboratories, 2 standards and 42 coded chemicals, including 23 phototoxins and 19 non-phototoxic drugs/chemicals, were assessed by the ROS assay using two different solar simulators (Atlas Suntest CPS series, 3 labs; and Seric SXL-2500V2, 4 labs). Irradiation conditions could be optimized using quinine and sulisobenzone as positive and negative standards to offer consistent assay outcomes. In both solar simulators, the intra- and inter-day precisions (coefficient of variation; CV) for quinine were found to be below 10%. The inter-laboratory CV for quinine averaged 15.4% (Atlas Suntest CPS) and 13.2% (Seric SXL-2500V2) for singlet oxygen and 17.0% (Atlas Suntest CPS) and 7.1% (Seric SXL-2500V2) for superoxide, suggesting high inter-laboratory reproducibility even though different solar simulators were employed for the ROS assay. In the ROS assay on 42 coded chemicals, some chemicals (ca. 19-29%) were unevaluable because of limited solubility and spectral interference. Although several false positives appeared with positive predictivity of ca. 76-92% (Atlas Suntest CPS) and ca. 75-84% (Seric SXL-2500V2), there were no false negative predictions in both solar simulators. A multi-center validation study on the ROS assay demonstrated satisfactory transferability, accuracy, precision, and predictivity, as well as the availability of other solar simulators.
Subject(s)
Laboratories/standards , Photosensitizing Agents/toxicity , Reactive Oxygen Species/metabolism , Sunlight , 3T3 Cells , Animals , Biological Assay , Mice , Photochemistry/methods , Photosensitizing Agents/chemistry , Reproducibility of Results , Ultraviolet RaysABSTRACT
A reactive oxygen species (ROS) assay was previously developed for photosafety evaluation of pharmaceuticals, and the present multi-center study aimed to establish and validate a standard protocol for ROS assay. In three participating laboratories, two standards and 42 coded chemicals, including 23 phototoxins and 19 nonphototoxic drugs/chemicals, were assessed by the ROS assay according to the standardized protocol. Most phototoxins tended to generate singlet oxygen and/or superoxide under UV-vis exposure, but nonphototoxic chemicals were less photoreactive. In the ROS assay on quinine (200 µm), a typical phototoxic drug, the intra- and inter-day precisions (coefficient of variation; CV) were found to be 1.5-7.4% and 1.7-9.3%, respectively. The inter-laboratory CV for quinine averaged 15.4% for singlet oxygen and 17.0% for superoxide. The ROS assay on 42 coded chemicals (200 µm) provided no false negative predictions upon previously defined criteria as compared with the in vitro/in vivo phototoxicity, although several false positives appeared. Outcomes from the validation study were indicative of satisfactory transferability, intra- and inter-laboratory variability, and predictive capacity of the ROS assay.
Subject(s)
Laboratories/standards , Pharmaceutical Preparations/radiation effects , Reactive Oxygen Species/analysis , Ultraviolet Rays , Validation Studies as Topic , Benzophenones/chemistry , Benzophenones/radiation effects , Dermatitis, Phototoxic/etiology , Dermatitis, Phototoxic/metabolism , Drug-Related Side Effects and Adverse Reactions/metabolism , Humans , Pharmaceutical Preparations/chemistry , Photochemical Processes , Quinine/chemistry , Quinine/radiation effects , Reference Standards , Reproducibility of Results , Ultraviolet Rays/adverse effectsABSTRACT
Two new sesquiterpenoid esters (1 and 2) were isolated from the extract of Blumea balsamifera, a tropical Compositae plant. Compound 2 proved to be weakly cytotoxic when tested against Jurkat human T-cell leukemia cells. Nine known flavonoids, of which two showed plasmin-inhibitory activity, were also isolated.
