Highly Potent HIV‑1 Protease Inhibitors with Novel Tricyclic P2 Ligands: Design, Synthesis, and Protein–Ligand X‑ray Studies

• Published in: Journal of medicinal chemistry Vol. 56; no. 17; pp. 6792 - 6802
• Main Authors: Ghosh, Arun K, Parham, Garth L, Martyr, Cuthbert D, Nyalapatla, Prasanth R, Osswald, Heather L, Agniswamy, Johnson, Wang, Yuan-Fang, Amano, Masayuki, Weber, Irene T, Mitsuya, Hiroaki
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.09.2013; Amer Chemical Soc; American Chemical Society (ACS)
• Subjects: Chemistry, Medicinal; Crystallography, X-Ray; HIV Protease - drug effects; HIV Protease - metabolism; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; Life Sciences & Biomedicine; Ligands; Magnetic Resonance Spectroscopy; Mass Spectrometry; Models, Molecular; Pharmacology & Pharmacy; Science & Technology; PI; GRL-0519; RESOLUTION CRYSTAL-STRUCTURES; DRUG-RESISTANT MUTANTS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400768f

The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor’s potent antiviral activity and excellent resistance profiles.