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.