A Conformationally Restricted -Strand HIV Protease Inhibitor

The use of cyclopropanes as a conformationally restricted subunits in biological systems has been the subject of intense study by our group and others (
1
–
10
). Our recent efforts have focused on the use of 1, 2, 3-trisubstituted cyclopropanes as novel [-NH-Cα-] or [-CO-Cα-] bond replacements in pseudopeptides to restrict both side-chain orientation and enforce backbone secondary structures. To test these assumptions, the cyclopropane containing analog
1
(Fig. 1 ) was modeled after the potent HIV protease inhibitor
2
, which together with a series of related derivatives was developed at Abbott Laboratories (
11
). This pseudopeptide contains a symmetrical diamino diol motif
8
(Fig. 2 ) flanked by Cbz-protected valine residues and is known to bind in a β-strand fashion at the enzyme-active site (
12
). Our analog
1
was designed to restrict the orientation of the valine residues and to mimic this “extended” backbone conformation. Comparison of enzyme inhibition constants for both compound
1
and the parent inhibitor
2
will then elucidate the efficacy of the cyclopropane as a conformationally restrictive subunit.Fig. 1.
HIV protease inhibitors.
Fig. 2.
Synthesis of the cyclopropane containing inhibitor 1.