Design and Synthesis of Potent HIV-1 Protease Inhibitors Incorporating Hexahydrofuropyranol-derived High Affinity P2 ligands: Structure-activity Studies and Biological Evaluation

摘要

The design, synthesis, and evaluation of a new series of hexahydrofuropyran-derived HIV-1 protease inhibitors are described. We have designed a stereochemically defined hexahydrofuropyranol-derived urethane as the P2-ligand. The current ligand is designed based upon the X-ray structure of >1a-bound HIV-1 protease. The synthesis of (3aS,4S,7aR)-hexahydro-2H-furo[2,3-b] pyran-4-ol (−)->7 was carried out in optically active form. Incorporation of this ligand provided inhibitor >35a, which has shown excellent enzyme inhibitory activity and antiviral potency. Our structure activity studies have indicated that the stereochemistry and the position of oxygens in the ligand are important to the observed potency of the inhibitor. Inhibitor >35a has maintained excellent potency against multidrug-resistant HIV-1 variants. An active site model of >35a was created based upon the X-ray structure of >1b-bound HIV-1 protease. The model offers molecular insights regarding ligand-binding site interactions of the hexahydrofuropyranol-derived novel P2-ligand.