New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl) (trifluoromethyl)pyrazoles and -pyrazolones.

Abstract

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.

• Authors: K L Kees, J J Fitzgerald Jr, K E Steiner, J F Mattes, B Mihan, T Tosi, D Mondoro, M L McCaleb
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 39 Issue 20 Pg. 3920-8 (Sep 27 1996) ISSN: 0022-2623 [Print] United States
• PMID: 8831758 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Membrane Glycoproteins
• Monosaccharide Transport Proteins
• Pyrazoles
• Slc5a1 protein, mouse
• Sodium-Glucose Transporter 1
• WAY 123783

Topics

• Absorption
• Animals
• Blood Glucose (metabolism)
• Diabetes Mellitus, Type 2 (blood, drug therapy)
• Glucose Tolerance Test
• Glycosuria
• Hypoglycemic Agents (chemical synthesis, therapeutic use)
• Kidney Tubules (metabolism)
• Membrane Glycoproteins (antagonists & inhibitors)
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Molecular Structure
• Monosaccharide Transport Proteins (antagonists & inhibitors)
• Pyrazoles (chemical synthesis, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Sodium-Glucose Transporter 1
• Structure-Activity Relationship