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. 2011 Jan 27;54(2):622-34.
doi: 10.1021/jm1012787. Epub 2010 Dec 31.

Design and synthesis of potent HIV-1 protease inhibitors incorporating hexahydrofuropyranol-derived high affinity P(2) ligands: structure-activity studies and biological evaluation

Arun K Ghosh  1 , Bruno D Chapsal, Abigail Baldridge, Melinda P Steffey, D Eric Walters, Yasuhiro Koh, Masayuki Amano, Hiroaki Mitsuya
Affiliations

Design and synthesis of potent HIV-1 protease inhibitors incorporating hexahydrofuropyranol-derived high affinity P(2) ligands: structure-activity studies and biological evaluation

Arun K Ghosh et al. J Med Chem. .

Abstract

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.

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Figures

Figure 1
Figure 1
Structures of inhibitors 1–3 and 35a.
Figure 2
Figure 2
Stereoview of inhibitor 35a, modeled into the active site of HIV-1 protease, and superimposed on the X-ray crystal structure of 1b (PDB code 3I7E).
Scheme 1
Scheme 1
Synthesis of ligand (−)-7 and its respective enantiomer (+)-7.
Scheme 2
Scheme 2
Synthesis of furocyclohexanol P2 ligand (−)-12
Scheme 3
Scheme 3
Syntheses of ligands (−)-18 and (−)-19.
Scheme 4
Scheme 4
Synthesis of hexahydrofuro[3,4-b]pyran-4-ol ligand 25.
Scheme 5
Scheme 5
Synthesis of hexahydrofuro[2,3-b]pyran-5-ol ligand 30
Scheme 6
Scheme 6
Synthesis of activated mixed carbonates 31a–g
Scheme 7
Scheme 7
Syntheses of inhibitors 35a–g, 36 and 37.
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