Abstract 349: Characterization of a New Organic Nitrate Hybrid Drug Covalently Bound to Pioglitazone
Background and Purpose: Organic nitrates represent a group of nitrovasodilators that are clinically used for the treatment of ischemic heart disease. With the present studies we synthesized and characterized a new organic nitrate hybrid molecule. Compound CLC-3000 is an aminoethyl nitrate (AEN) derivative of pioglitazone, a thiazolidinedione antidiabetic agent. This new molecular entity combines the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activity of pioglitazone with the NO-donating activity of the nitrate moiety. Experimental Approach: In vitro and in vivo characterization was performed by isometric tension recording, bleeding time and detection of oxidative stress.
Key Results: The vasodilative potency of CLC-3000 in vitro was shown to be markedly superior to that of pioglitazone alone or a classical nitrate, although in vitro, at high concentrations, some effects on oxidative stress parameters were observed. Following seven days exposure to CLC-3000 in vivo, no change was seen in the vasodilative response of rat aortic rings towards acetylcholine, nitroglycerin or CLC-3000 itself. Similarly, no remarkable increase in oxidative stress parameters was observed under CLC-3000 therapy. Acute or chronic administration of AEN decreased the tail vein bleeding time in mice.
Conclusions and Implications: In summary, the results of these studies demonstrate that CLC-3000 contains a vasodilative and anti-thrombotic activity that is not evident with pioglitazone alone, and that seven days exposure in vivo showed no typical signs of nitrate tolerance, endothelial dysfunction or other safety concerns in Wistar rats.
Author Disclosures: A. Pfeffer: None. M. Knorr: None. M. Hausding: None. T. Jansen: None. M. Oelze: None. S. Kröller-Schön: None. E. Schulz: None. P. Wenzel: None. T. Gori: None. T. Muenzel: Research Grant; Significant; research grant support by Cardiolynx AG, Basel, CH. A. Daiber: Research Grant; Significant; research grant support by Cardiolynx AG, Basel, CH. Honoraria; Modest; speaker honoraria. Consultant/Advisory Board; Modest; consultant honoraria.
- © 2014 by American Heart Association, Inc.