New generation angiotensin II type 1 receptor antagonists that selectively modulate peroxisome proliferator‐activated receptor‐γ

The discovery that the antihypertensive angiotensin II type 1 receptor (AT1R) blockers (ARBs), telmisartan and irbesartan, were capable of activating peroxisome proliferators‐activated receptor (PPAR)‐γ has provided a novel approach for developing new generation ARBs with beneficial metabolic effects. By selectively blocking the angiotensin II–mediated pro‐inflammatory AT1R signaling pathway, while activating the PPARγ‐dependent anti‐inflammatory pathway, these compounds may confer broader anti‐inflammatory protection compared to other ARBs, i.e., those lacking PPARγ activity. Both telmisartan and irbesartan function as selective PPARγ modulators. Their potential beneficial effects beyond blood pressure reduction, include increased insulin sensitivity, improved lipid profile, improved anti‐inflammatory, and anti‐atherogenic risk profiles. These properties could provide superior clinical efficacy in hypertensive patients with insulin‐resistant states such as the metabolic syndrome and type 2 diabetes. Thus, among existing ARBs, telmisartan and irbesartan may have added benefits in the treatment of cardiovascular diseases with metabolic pathology, and their associated end‐organ microvascular and macrovascular complications. This unique subset of ARBs provides a strategic platform for designing prototypes of a new class of PPARγ ligands capable of antagonizing AT1R, for broadly targeting cardiometabolic diseases for which therapy is presently insufficient or non‐existent. Drug Dev. Res. 67:687;–697, 2006.