gw-7647 and Hypertension

Metabolic syndrome (MetS) is a multifactorial disease cluster that consists of dyslipidemia, cardiovascular disease, type 2 diabetes mellitus, and obesity. MetS patients are strongly exposed to polypharmacy; however, the number of pharmacological compounds required for MetS treatment can be reduced by the application of multitarget compounds. This study describes the design of dual-target ligands that target soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated receptor type γ (PPARγ). Simultaneous modulation of sEH and PPARγ can improve diabetic conditions and hypertension at once. N-Benzylbenzamide derivatives were determined to fit a merged sEH/PPARγ pharmacophore, and structure-activity relationship studies were performed on both targets, resulting in a submicromolar (sEH IC50 = 0.3 μM/PPARγ EC50 = 0.3 μM) modulator 14c. In vitro and in vivo evaluations revealed good ADME properties qualifying 14c as a pharmacological tool compound for long-term animal models of MetS.

Topics: 3T3 Cells; Administration, Oral; Animals; Benzamides; Chlorocebus aethiops; COS Cells; Diabetes Mellitus, Type 2; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Hypertension; In Vitro Techniques; Metabolic Syndrome; Mice; Microsomes, Liver; PPAR gamma; Rats; Structure-Activity Relationship