Optimization of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of HIV capsid assembly inhibitors 2: Structure–activity relationships (SAR) of the C3-phenyl moiety

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 11; pp. 3401 - 3405
• Main Authors: Fader, Lee D., Landry, Serge, Goulet, Sylvie, Morin, Sébastien, Kawai, Stephen H., Bousquet, Yves, Dion, Isabelle, Hucke, Oliver, Goudreau, Nathalie, Lemke, Christopher T., Rancourt, Jean, Bonneau, Pierre, Titolo, Steve, Amad, Ma’an, Garneau, Michel, Duan, Jianmin, Mason, Stephen, Simoneau, Bruno
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-06-2013
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Benzodiazepine; Benzodiazepines - chemical synthesis; Benzodiazepines - chemistry; Benzodiazepines - pharmacology; Benzodiazepinones - chemical synthesis; Benzodiazepinones - chemistry; Benzodiazepinones - pharmacology; Binding Sites; Caco-2 Cells; capsid; Capsid Assembly Inhibitor; Capsid Proteins - antagonists & inhibitors; Capsid Proteins - metabolism; Cell Membrane Permeability - drug effects; coat proteins; Crystallography, X-Ray; HIV; HIV-1 - metabolism; Human immunodeficiency virus; Humans; Immature Gag assembly Inhibitor; Protein Structure, Tertiary; Stereoisomerism; Structure-Activity Relationship; structure-activity relationships; Virus Assembly - drug effects; HIV; Capsid Assembly Inhibitor; Immature Gag assembly Inhibitor; Benzodiazepine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.03.074

Detailed structure–activity relationships of the C3-phenyl moiety that allow for the optimization of antiviral potency of a series of 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione inhibitors of HIV capsid (CA) assembly are described. Combination of favorable substitutions gave additive SAR and allowed for the identification of the most potent compound in the series, analog 27. Productive SAR also transferred to the benzotriazepine and spirobenzodiazepine scaffolds, providing a solution to the labile stereocenter at the C3 position. The molecular basis of how compound 27 inhibits mature CA assembly is rationalized using high-resolution structural information. Our understanding of how compound 27 may inhibit immature Gag assembly is also discussed.