K-111 has been characterized as a potent
peroxisome proliferator-activated receptor (
PPAR)alpha activator.
Antidiabetic potency and amelioration of disturbed lipid metabolism were demonstrated in rodents, which were accompanied by elevations of peroxisomal
enzymes and liver weight. To examine the possible therapeutic application of
K-111 we have now assessed its efficacy in non-human primates with high transferability to humans. For this purpose obese, hypertriglyceridaemic, hyperinsulinaemic prediabetic rhesus monkeys were dosed sequentially with 0, 1, 3 and 10mg/kg per day orally over a period of 4 weeks each. In addition, the effect of
K-111 on the peroxisome compartment was analyzed in cynomolgus monkeys using liver samples obtained following a 13-week oral toxicity study. In prediabetic monkeys, the reduction of hyperinsulinaemia and improvement of
insulin-stimulated
glucose uptake rate indicated amelioration of
insulin resistance. These effects were nearly maximal at a dose of 3mg/kg per day, while
triglycerides and
body weight were lowered significantly in a dose-dependent manner. This reduction of
body weight contrasts sharply with the adipogenic response observed with
thiazolidinediones, another family of
insulin-sensitizing agents. In young cynomolgus monkeys at a dosage of 5mg/kg per day and more,
K-111 induced an up to three-fold increase in
lipid beta-oxidation
enzymes with an 1.5- to 2-fold increase in peroxisome volume density. This moderate increase in peroxisomal activity by
K-111 in monkeys is consistent with its role as an
PPARalpha activator and corresponds to the observations with
fibrates in other low responder mammalian species. The increase in beta-oxidation may explain, at least in part, the
lipid modulating effect as well as the
antidiabetic potency of
K-111. This pharmacological profile makes
K-111 a highly promising
drug candidate for clinical applications in the treatment of
type 2 diabetes, dyslipidaemia,
obesity and the
metabolic syndrome.