PubMed · 4924725
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G C Ceschel, F Fontani. 1970. [Operculated capsules].. https://pubmed.ncbi.nlm.nih.gov/4924725/
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The synthesis, structure-activity relationship (SAR) studies, and antidiabetic characterization of 1,2-dihydro-4-[[4-(methylthio)phenyl]methyl]-5-(trifluoromethyl)-3H- pyrazol-3-one (as the hydroxy tautomer; WAY-123783, 4) are described. Substitution of 4-methylthio, methylsulfinyl, or ethyl to a benzyl group at C4, in combination with trifluoromethyl at C5 of pyrazol-3-one, generated potent antihyperglycemic agents in obese, diabetic db/db mice (16-30% reduction in plasma glucose at 2 mg/kg). The antihyperglycemic effect was associated with a robust glucosuria (> 8 g/dL) observed in nondiabetic mice. Chemical trapping of four of the seven possible tautomeric forms of the heterocycle by mono- and dialkylation at the acidic hydrogens provided several additional potent analogs (39-43% reduction at 5 mg/kg) of the lead 4 as well as a dialkylated pair of regioisomers that showed separation of the associated glucosuric effect produced by all of the active analogs in normal mice. Further pharmacological characterization of the lead WAY-123783 (ED50 = 9.85 mg/kg, po in db/db mice), in oral and subcutaneous glucose tolerance tests, indicated that unlike the renal and intestinal glucose absorption inhibitor phlorizin, pyrazolone 4 does not effectively block intestinal glucose absorption. SAR and additional pharmacological data reported herein suggest that WAY-123783 represents a new class of potent antihyperglycemic agents which correct hyperglycemia by selective inhibition of renal tubular glucose reabsorption.
BACKGROUND: Carcinoembryonic antigen (CEA) is used as a serum marker to detect and monitor the status of various kinds of malignant tumors. To determine whether CEA might be detected in secretions collected topically from around the nipple area, and whether its secretion might differ in a cancerous versus a noncancerous breast, we developed a simple method for collecting and measuring CEA, using a small cellulose membrane disk and an enzyme immunoassay. METHODS: We measured the amount of CEA excreted from the nipple area of 22 healthy control women and 32 women with unilateral breast carcinoma confirmed histologically. Secretions were collected from the nipple area by affixing a small (20 mm diameter) absorbent disk made of nitrocellulose membrane backed with filter paper to that area for 24 hours. Substances absorbed by the membrane were then subjected to an immunoassay for CEA using anti-CEA antibodies. RESULTS: In the 22 healthy subjects, a small amount of CEA (0.6 +/- 0.9 units) was secreted from each nipple, which was equally low regardless of the phase of the menstrual cycle. In contrast, 30 of the 32 women with breast carcinoma secreted significantly greater amounts of CEA from the cancerous (16.1 +/- 8.2) than the noncancerous (2.0 +/- 2.2) breast. Such a difference (14.1 +/- 8.0) in CEA excretion was not observed in the healthy controls (0 +/- 0). CONCLUSIONS: These findings suggest that such disks may provide a simple and noninvasive method of collecting trace molecules, including CEA, in skin secretions around the nipple to evaluate functional disorders of the mammary glands, particularly breast carcinoma. Additional studies are indicated in larger groups of women with various stages of breast carcinoma as well as with benign breast diseases.
A series of azetidinone cholesterol absorption inhibitors related to SCH 48461 ((-)-6) has been prepared, and compounds were evaluated for their ability to inhibit hepatic cholesteryl ester formation in a cholesterol-fed hamster model. Although originally designed as acyl CoA: cholesterol acyltransferase (ACAT) inhibitors, comparison of in vivo potency with in vitro activity in a microsomal ACAT assay indicates no correlation between activity in these two models. The molecular mechanism by which these compounds inhibit cholesterol absorption is unknown. Despite this limitation, examination of the in vivo activity of a range of compounds has revealed clear structure-activity relationships consistent with a well-defined molecular target. The details of these structure-activity relationships and their implications on the nature of the putative pharmacophore are discussed.