Long-Acting Angiotensin II Inhibitors Containing Hexafluorovaline in Position 8

An improved synthesis of hexafluorovaline (Hfv) derivatives, i.e., DL-Hfv-OBzl and Boc-DL-Hfv, is described. Incorporation of hexafluorovaline into angiotensin resulted in [Sar¹,Hfv⁸]AII and [Sar¹,D-Hfv⁸] AII. At the nanogram/milliliter dose range, the L congener was 20–100 times more active as either angiotensin agonist or angiotensin antagonist than its D diastereomer on isolated tissue preparations. At the microgram dose range, both [Sar¹,Hfv⁸]AII and [Sar¹,D-Hfv⁸]AII were significantly more effective than [Sar¹,Leu⁸]AII as angiotensin II inhibitors, producing prolonged blockade of the pressor response toward angiotensin II for over 1 h.