The effect of 1,3-diaryl-[1H]-pyrazole-4-acetamides on glucose utilizationin ob/ob mice

This article provides evidence of a new class of compounds, 1,3-diaryl-[1H] -pyrazole-4-acetamides, initially identified from their ability to increase glucose transport in an adipocyte and muscle cell line and ultimately demo nstrating dramatic glucose lowering in ob/ob Mice, a diabetic animal model. The lead compound, 1, possessed some behavioral-like effects which were re moved by structural variation during the course of this investigation. Spec ifically, 11 g (RI = meta-CF3, Ar2 = 4 ' biphenyl, R3 = diethylamide) illus trated the potency of this series with ED50 values for glucose lowering in ob/ob mice of 3.0 mg/kg/day. Concomitant with its effect on glucose lowerin g, 11g also caused a 50% reduction in insulin levels consistent with an age nt that increases whole body insulin sensitivity. 11g showed favorable phar macokinetic data with acceptable absorption, negligible metabolism, and goo d duration of action. 11g demonstrated no appreciable adipogenic effect thr ough PPAR gamma agonism, a characteristic of the thiazolidinediones (TZD), and so represents a potentially new class of agents for the treatment of di abetes.