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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
20
|
| pubmed:dateCreated |
1996-11-14
|
| pubmed:abstractText |
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.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Blood Glucose,
http://linkedlifedata.com/resource/pubmed/chemical/Hypoglycemic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Monosaccharide Transport Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Slc5a1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Sodium-Glucose Transporter 1
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Sep
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
27
|
| pubmed:volume |
39
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
3920-8
|
| pubmed:dateRevised |
2005-11-17
|
| pubmed:meshHeading |
pubmed-meshheading:8831758-Absorption,
pubmed-meshheading:8831758-Animals,
pubmed-meshheading:8831758-Blood Glucose,
pubmed-meshheading:8831758-Diabetes Mellitus, Type 2,
pubmed-meshheading:8831758-Glucose Tolerance Test,
pubmed-meshheading:8831758-Glycosuria,
pubmed-meshheading:8831758-Hypoglycemic Agents,
pubmed-meshheading:8831758-Kidney Tubules,
pubmed-meshheading:8831758-Membrane Glycoproteins,
pubmed-meshheading:8831758-Mice,
pubmed-meshheading:8831758-Mice, Inbred C57BL,
pubmed-meshheading:8831758-Mice, Obese,
pubmed-meshheading:8831758-Molecular Structure,
pubmed-meshheading:8831758-Monosaccharide Transport Proteins,
pubmed-meshheading:8831758-Pyrazoles,
pubmed-meshheading:8831758-Rats,
pubmed-meshheading:8831758-Rats, Sprague-Dawley,
pubmed-meshheading:8831758-Sodium-Glucose Transporter 1,
pubmed-meshheading:8831758-Structure-Activity Relationship
|
| pubmed:year |
1996
|
| pubmed:articleTitle |
New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl) (trifluoromethyl)pyrazoles and -pyrazolones.
|
| pubmed:affiliation |
Department of Medicinal Chemistry, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000, USA.
|
| pubmed:publicationType |
Journal Article
|