John Patrick Mogensen

Design and synthesis of novel PPARα/γ/δ triple activators using a known PPARα/γ dual activator as structural template

Abstract Using a known dual PPARα/γ activator (5) as a structural template, SAR evaluations led to the identification of triple PPARα/γ/δ activators (18–20) with equal potency and efficacy on all three receptors. These compounds could become useful tools for studying the combined biological effects of PPARα/γ/δ activation.

Selective PPAR agonists for the treatment of type 2 diabetes

Abstract:  Type 2 diabetes is a metabolic disease characterized by increased plasma glucose and insulin as well as dyslipidemia. If left untreated, chronic diseases will develop that are associated with neuropathic damage and higher mortality risk. Using a rational drug design, novel compounds have been developed that selectively activate the human PPAR receptors, leading to lessening of hyperglycemia and hyperinsulinemia as well as reduction of lipid levels in conjunction with an increase of the beneficial HDL‐cholesterol. These PPAR agonists showed increased potency and efficacy compared to previously marketed insulin sensitizers. Lead compounds with desirable pharmacokinetic properties were chosen for further testing in several animal models. The in vivo activity of some synthetic ligands, capable of activating two or all three members of peroxisome proliferator‐activated receptors (PPAR) family of receptors, suggested that they may have improved efficacy in type 2 diabetes therapy. Here, we briefly summarize the development of some novel PPAR agonists identified by our group in recent years.

Mesolimbic selective antipsychotic arylcarbamates

Abstract 4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidine has been linked to various arylcarbamates to obtain compounds having affinity for dopamine-D 1 and -D 2 , serotonin 5HT 2A and α 1 -adrenoceptors. When linkers with restricted flexibility are used, the biological activity is reduced indicating that a bended conformation is needed in this series of bioactive molecules. Compounds with a relatively low D 2 /5HT 2A affinity ratio in receptor binding experiments and high affinity for the α 1 -adrenoceptors exhibit a pharmacological profile which suggests a preferential effect on the mesocorticolimbic dopaminergic system and an ‘atypical’ antipsychotic activity.

Phenylcyanoguanidines as inhibitors of glucose-induced insulin secretion from beta cells

3,5-Disubstituted-phenylcyanoguanidines have been identified as activators of SUR1/Kir6.2 potassium channels and as potent inhibitors of insulin release from pancreatic beta cells in vitro.