US EPA

7458637 

Journal Article 

Design of HIV-1 protease inhibitors with C3-substituted hexahydrocyclopentafuranyl urethanes as P2-ligands: Synthesis, biological evaluation, and protein-ligand X-ray crystal structure 

Ghosh, AK; Chapsal, BD; Parham, GL; Steffey, M; Agniswamy, J; Wang, YF; Amano, M; Weber, IT; Mitsuya, H 

2011 

Yes 

Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 

54 

16 

5890-5901 

English 

10.1021/jm200649p 

We report the design, synthesis, biological evaluation, and the X-ray crystal structure of a novel inhibitor bound to the HIV-1 protease. Various C3-functionalized cyclopentanyltetrahydrofurans (Cp-THF) were designed to interact with the flap Gly48 carbonyl or amide NH in the S2-subsite of the HIV-1 protease. We investigated the potential of those functionalized ligands in combination with hydroxyethylsulfonamide isosteres. Inhibitor 26 containing a 3-(R)-hydroxyl group on the Cp-THF core displayed the most potent enzyme inhibitory and antiviral activity. Our studies revealed a preference for the 3-(R)-configuration over the corresponding 3-(S)-derivative. Inhibitor 26 exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray structure of 26-bound HIV-1 protease revealed important molecular insight into the ligand-binding site interactions. © 2011 American Chemical Society. 

3 hydroxyhexahydro 2h cyclopenta[b]furan 5 yl [3 hydroxy 4 (n isobutyl 4 methoxyphenylsulfonamido) 1 phenylbutan 2 yl]carbamate; amide; carbonyl derivative; cyclopentane derivative; glycine; Human immunodeficiency virus proteinase; hydroxyl group; ligand; proteinase inhibitor; sulfonamide; unclassified drug; urethan derivative; antiviral activity; article; crystal structure; drug binding site; drug potency; drug protein binding; drug screening; drug synthesis; enzyme active site; enzyme inhibition; Human immunodeficiency virus 1; ligand binding; multidrug resistance; nonhuman; structure activity relation; Amino Acid Substitution; Binding Sites; Biocatalysis; Cell Line; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Ligands; Models, Chemical; Models, Molecular; Molecular Structure; Mutation; Protein Binding; Protein Structure, Tertiary; Structure-Activity Relationship; Urethane