Structure-activity relationships in a series of C2-symmetric HIV-protease inhibitors

Abstract

Publisher Summary This chapter describes a series of inhibitors in which a central building block, containing a transition-state mimetic and the P1 and P1’ residues of the HIV-PR cleavage site, is placed in a C 2 -symmetrical peptidic environment and it presents a detailed structure-activity relationship (SAR) for both enzyme inhibition and in vitro activity. The synthesis of the symmetric diamino diol moiety of HOE/BAY 793 is accomplished either by reductive pinacol coupling of N-protected phenylalaninal with SmI 2 or using a mannitol-based bisepoxide which is reacted with (C 6 H 5 ) 2 CuLi. Starting from this central building block, the side chains containing P2, P2’, P3, P3’ are introduced using standard peptide chemistry. These prodrugs release HOE/BAY 793 in a cyclization reaction, which is either only chemically driven or which can be preceded by an enzymatic cleavage. Regarding the inhibition of HIV-PR the phosphinic acid containing inhibitors behave very similar to the diol containing inhibitors with respect to the filling of the P1, P2, and P3 sites.