Synthesis and comparative molecular field analysis (CoMFA) of symmetric and nonsymmetric cyclic sulfamide HIV-1 protease inhibitors

We have previously reported on the unexpected flipped conformation in the c yclic sulfamide class of inhibitors. An attempt to induce a symmetric bindi ng conformation by introducing P2/P2' substituents foreseen to bind prefere ntially in the S2/S2' subsite was unsuccessful. On the basis of the flipped conformation we anticipated that nonsymmetric sulfamide inhibitors, with P 2/P2' side chains modified individually for the S1' and S2 subsites, should be more potent than the corresponding symmetric analogues. To test this hy pothesis, a set of 18 cyclic sulfamide inhibitors (11 nonsymmetric and 7 sy mmetric) with different P2/P2' substituents was prepared and evaluated in a n enzyme assay. To rationalize the structure-activity relationship (SAR) an d enable the alignment of the nonsymmetric inhibitors, i.e., which of the P 2/P2' substituents of the nonsymmetric inhibitors interact with which subsi te, a CoMFA study was performed. The CoMFA model, constructed from the 18 i nhibitors in this study along with seven inhibitors from previous work by o ur group, has successfully been used to rationalize the SAR of the cyclic s ulfamide inhibitors. Furthermore, from the information presented herein, th e SAR of the cyclic sulfamide class of inhibitors seems to differ from the SAR of the related cyclic urea inhibitors reported by DuPont and DuPont-Mer ck.