Brian R. Boettcher

Cevoglitazar, a Novel Peroxisome Proliferator-Activated Receptor-α/γ Dual Agonist, Potently Reduces Food Intake and Body Weight in Obese Mice and Cynomolgus Monkeys

Cevoglitazar is a dual agonist for the peroxisome proliferator-activated receptor (PPAR)-alpha and -gamma subtypes. Dual activation of PPARalpha and -gamma is a therapeutic approach in development for the treatment of type 2 diabetes mellitus and diabetic dyslipidemia. In this report, we show that, in addition to improving insulin sensitivity and lipid metabolism like other dual PPAR agonists, cevoglitazar also elicits beneficial effects on energy homeostasis in two animal models of obesity. In leptin-deficient ob/ob mice, administration of cevoglitazar at 0.5, 1, or 2 mg/kg for 18 d led to acute and sustained, dose-dependent reduction of food intake and body weight. Furthermore, plasma levels of glucose and insulin were normalized after 7 d of cevoglitazar treatment at 0.5 mg/kg. Plasma levels of free fatty acids and triglycerides were dose-dependently reduced. In obese and insulin-resistant cynomolgus monkeys, treatment with cevoglitazar at 50 and 500 mug/kg for 4 wk lowered food intake and body weight in a dose-dependent manner. In these animals, cevoglitazar also reduced fasting plasma insulin and, at the highest dose, reduced hemoglobin A1c levels by 0.4%. These preclinical results demonstrate that cevoglitazar holds promise for the treatment of diabetes and obesity-related disorders because of its unique beneficial effect on energy balance in addition to improving glycemic and metabolic control.

N-Hydroxyglycine derivatives as novel inhibitors of squalene synthase

Abstract The squalene synthase inhibiting properties of farnesyl diphosphate (FPP) mimics, 3 and related analogues, are described. The results indicate that the nonphosphorus-containing N-hydroxyglycine is a novel replacement for the diphosphate group. Further optimization of 3 has led to 12 , a new and potent squalene synthase inhibitor.

Peptide mimics of glycylproline as inhibitors of prolidase

Abstract Aminoketone 1 , a ψ[COCH] dipeptide mimic of glycylproline, is a potent, competitive inhibitor (K i = 270 ± 24 nM) of porcine kidney prolidase, a Mn(II)-dependent dipeptidase, whereas the homologous aminoketone 2 and its non-cyclic analogue δ-amino-levulinic acid, 3 , are significantly less inhibitory (K i ≈ 1 mM).