Discovery of imidazolidine-2,4-dione-linked HIV protease inhibitors with activity against lopinavir-resistant mutant HIV

• Published in: Bioorganic & medicinal chemistry 2006-10, Vol.14 (19), p.6695-6712
• Main Authors: Flosi, William J., DeGoey, David A., Grampovnik, David J., Chen, Hui-ju, Klein, Larry L., Dekhtyar, Tatyana, Masse, Sherie, Marsh, Kennan C., Mo, Hong Mei, Kempf, Dale
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Crystallography, X-Ray; Drug Design; Drug Resistance, Viral; HIV; HIV Infections - virology; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - pharmacology; HIV resistance; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus 1; Humans; Imidazolidine-2,4-dione; Imidazolidines - chemical synthesis; Imidazolidines - pharmacology; Lopinavir; Magnetic Resonance Spectroscopy; Medical sciences; Mutation; Pharmacology. Drug treatments; Protease inhibitor; Pyrimidinones - pharmacology; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.05.063

A series of HIV protease inhibitors containing various cyclic structural motifs (Q) which occupy subsite S2 of HIV protease and facilitate the access of P3 groups into subsite S3 via a N-methylene linker was designed and evaluated for their antiviral activity against wild-type HIV virus with and without human serum. Promising compounds were further screened against resistant strains of HIV. In addition, the pharmacokinetic properties in rats were studied. A new series of HIV protease inhibitors has been designed and synthesized based on the combination of the (R)-(hydroxyethylamino)sulfonamide isostere and the cyclic urea component of lopinavir. The series was optimized by replacing the 6-membered cyclic urea linker with an imidazolidine-2,4-dione which readily underwent N-alkylation to incorporate various methylene-linked heterocycle groups that bind favorably in site 3 of HIV protease. Significant improvements compared to lopinavir were seen in cell culture activity versus wild-type virus (pNL4-3) and the lopinavir-resistant mutant virus A17 (generated by in vitro serial passage of HIV-1 (pNL4-3) in MT-4 cells). Select imidazolidine-2,4-dione containing PIs were also more effective at inhibiting highly resistant patient isolates Pt1 and Pt2 than lopinavir. Pharmacokinetic data collected for compounds in this series varied considerably when coadministered orally in the rat with an equal amount of ritonavir (5mg/kg each). The AUC values ranged from 0.144 to 12.33μgh/mL.