STUDIES ON NEW ACIDIC AZOLES AS GLUCOSE-LOWERING AGENTS IN OBESE, DIABETIC DB DB MICE/

Bioisosteric substitution was used as a tool to generate several new s tructural alternatives to the thiazolidine-2,4-dione and tetrazole het erocycles as potential antidiabetic agents. Among the initial leads th at emerged from this strategy, a family of acidic azoles isoxazol-3- a nd -5-ones and a pyrazol-3-one, showed significant plasma glucose-lowe ring activity (17-42% reduction) in genetically obese, diabetic db/db mice at a dose of 100 mg/kg/day x 4. Structure-activity relationship s tudies determined that 5-alkyl-4-(arylmethyl)pyrazol-3-ones, which exi st in solution as aromatic enol/iminol tautomers, were the most promis ing new class of potential antidiabetic agent (32-45% reduction at 20 mg/kg/d x 4). Included in this work are convenient syntheses for sever al types of acidic azoles that may find use as new acidic bioisosteres in medicinal chemistry such as the antidiabetic lead 5-(trifluorometh yl)pyrazol-3-one (hydroxy tautomer) and aza homologs of the pyrazolone s, 1,2,3-triazol-5-ones (hydroxy tautomer) and 1,2,3,4-tetrazol-5-one heterocycles. log P and pK(a) data for 15 potential acidic bioisostere s, all appended to a 2-naphthalenylmethyl residue so as to maintain a similar distance between the acidic hydrogen and arene nucleus, are pr esented. This new data set allows comparison of a wide variety of pote ntial acid mimetics (pK(a) 3.78-10.66; log P -0.21 to 2.76) for future drug design.