- FUSED 6,5 BICYCLIC RING SYSTEM P2 LIGANDS, AND METHODS FOR TREATING HIV
-
Inhibitors of HIV-1 protease and compositions containing them are described. Use of the inhibitors and compositions containing them to treat HIV, AIDS, and AIDS-related diseases is described.
- -
-
-
- Design and synthesis of potent HIV-1 protease inhibitors incorporating hexahydrofuropyranol-derived high affinity P2 ligands: Structure-activity studies and biological evaluation
-
The design, synthesis, and evaluation of a new series of hexahydrofuropyranol-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.
- Ghosh, Arun K.,Chapsal, Bruno D.,Baldridge, Abigail,Steffey, Melinda P.,Walters, D. Eric,Koh, Yasuhiro,Amano, Masayuki,Mitsuya, Hiroaki
-
p. 622 - 634
(2011/03/21)
-
- METHOD AND COMPOSITIONS FOR TREATING HIV INFECTIONS
-
Described herein are compounds and compositions that are useful in the treatment of HIV, AIDS, and AIDS-related diseases. In addition, compounds are described herein that are capable of inhibiting the dimerization of HIV proteases.
- -
-
-