title: Studies on new acidic azoles as glucose-lowering agents in obese, diabetic db/db mice.
abstract: Bioisosteric substitution was used as a tool to generate several new structural alternatives to the thiazolidine-2,4-dione and tetrazole heterocycles as potential antidiabetic agents. Among the initial leads that emerged from this strategy, a family of acidic azoles, isoxazol-3- and -5-ones and a pyrazol-3-one, showed significant plasma glucose-lowering activity (17-42% reduction) in genetically obese, diabetic db/db mice at a dose of 100 mg/kg/day x4. Structure-activity relationship studies determined that 5-alkyl-4-(arylmethyl)pyrazol-3-ones, which exist in solution as aromatic enol/iminol tautomers, were the most promising new class of potential antidiabetic agent (32-45% reduction at 20 mg/kg/d x4). Included in this work are convenient syntheses for several types of acidic azoles that may find use as new acidic bioisosteres in medicinal chemistry such as the antidiabetic lead 5-(trifluoromethyl)pyrazol-3-one (hydroxy tautomer) and aza homologs of the pyrazolones, 1,2,3-triazol-5-ones (hydroxy tautomer) and 1,2,3,4-tetrazol-5-one heterocycles. log P and pKa data for 15 potential acidic bioisosteres, all appended to a 2-naphthalenylmethyl residue so as to maintain a similar distance between the acidic hydrogen and arene nucleus, are presented. This new data set allows comparison of a wide variety of potential acid mimetics (pKa 3.78-10.66; log P -0.21 to 2.76) for future drug design.
authors.affiliation: Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
authors.forename: K L
authors.initials: KL
authors.lastname: Kees
authors.forename: T J
authors.initials: TJ
authors.lastname: Caggiano
authors.forename: K E
authors.initials: KE
authors.lastname: Steiner
authors.forename: J J
authors.initials: JJ
authors.lastname: Fitzgerald
authors.forename: M J
authors.initials: MJ
authors.lastname: Kates
authors.forename: T E
authors.initials: TE
authors.lastname: Christos
authors.forename: J M
authors.initials: JM
authors.lastname: Kulishoff
authors.forename: R D
authors.initials: RD
authors.lastname: Moore
authors.forename: M L
authors.initials: ML
authors.lastname: McCaleb
mesh_terms: D000818:Animals; D001393:Azoles / Q000737:chemistry / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D013329:Structure-Activity Relationship
chemical_list: D001393:Azoles; D001786:Blood Glucose; D007004:Hypoglycemic Agents