Lipid Masking and Reactivation of Angiotensin Analogues

Studies on post-angioplastic restenosis have shown the implication of angiotensin II (Ang) as a myoproliferative mediator. The antiproliferative efficacy of non-peptide Ang antagonists on the rat carotid model is of 50%, whereas a continuously infused peptide antagonist at low doses totally blocks neointimal growth. To explore the feasibility of depot forms of Ang that may be introduced during angioplasty and thus prevent restenois, lipid-masked Ang analogues of the following general structure were prepared: [Xxx°, Yyy¹]Ang with Xxx = decanoyl or palmitoyl and Yyy = Ser, Cys, Asp, β-lactoyl, 3-mercaptopropanoyl or succinyl. All fatty acylated peptides [Xxx°, Yyy¹]Ang were practically inactive, and O- or S-esterified Ser and Cys peptides underwent intramolecular transcylation giving inactive N^x-acylated peptides. O-Acylated [β-mercaptopropanoyl¹]Ang were easily hydrolyzed into their biologically active[Yyy¹]Ang forms, either by mild saponification or by lipase activity.