Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1′-P2′ ligands

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 21; pp. 4925 - 4931
• Main Authors: Ghosh, Arun K., Sean Fyvie, W., Brindisi, Margherita, Steffey, Melinda, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Amano, Masayuki, Weber, Irene T., Mitsuya, Hiroaki
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.11.2017; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Binding Sites; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Drug Design; Drug resistance; HIV protease; HIV Protease - chemistry; HIV Protease - genetics; HIV Protease - metabolism; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - metabolism; HIV-1 - enzymology; Inhibitory Concentration 50; Life Sciences & Biomedicine; Ligands; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - metabolism; Macrocyclic inhibitors; Molecular Dynamics Simulation; Mutation; P1′-P2′ ligands; Pharmacology & Pharmacy; Physical Sciences; Protein Structure, Tertiary; Pyrrolidinones - chemistry; Science & Technology; Structure-Activity Relationship; Structure-based design; P1′-P2′ ligands; Drug resistance; HIV protease; Macrocyclic inhibitors; Structure-based design; P1 '-P2 ' ligands; POTENT; ACTIVE ANTIRETROVIRAL THERAPY; TMC114; PI; INFECTION; DRUG-RESISTANCE; BACKBONE
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.09.003

[Display omitted] Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1′-P2′ tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki=13.2nM, IC50=22nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (Ki=62pM and 14pM, respectively) and antiviral activity (IC50=5.3nM and 2.0nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.