Discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 1; pp. 398 - 404
• Main Authors: Fader, Lee D., Bethell, Richard, Bonneau, Pierre, Bös, Michael, Bousquet, Yves, Cordingley, Michael G., Coulombe, René, Deroy, Patrick, Faucher, Anne-Marie, Gagnon, Alexandre, Goudreau, Nathalie, Grand-Maître, Chantal, Guse, Ingrid, Hucke, Oliver, Kawai, Stephen H., Lacoste, Jean-Eric, Landry, Serge, Lemke, Christopher T., Malenfant, Eric, Mason, Stephen, Morin, Sébastien, O’Meara, Jeff, Simoneau, Bruno, Titolo, Steve, Yoakim, Christiane
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.01.2011; Elsevier
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Benzodiazepine; Benzodiazepinones - chemical synthesis; Benzodiazepinones - chemistry; Benzodiazepinones - pharmacology; Biological and medical sciences; Capsid assembly inhibitor; Capsid Proteins - antagonists & inhibitors; Capsid Proteins - metabolism; Drug Evaluation, Preclinical; HIV; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; Human immunodeficiency virus 1; Humans; Imidazoles - chemistry; Medical sciences; Pharmacology. Drug treatments; Pyrazoles - chemistry; Reverse transcriptase inhibitor; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship; Capsid assembly inhibitor; HIV; Reverse transcriptase inhibitor; Benzodiazepine; RNA-directed DNA polymerase; HIV-1 virus; Enzyme; Transferases; Lactam; Retroviridae; Enzyme inhibitor; Lentivirus; In vitro; Virus; Imidazobenzodiazepine derivatives; Nucleotidyltransferases; Structure activity relation; Chlorine Organic compounds; Antiviral; Benzodiazepine derivatives; Human immunodeficiency virus; Fluorine Organic compounds; Capsid; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.10.131

The discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly is described. Synthesis of analogs of the 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hit established structure–activity relationships. Replacement of the enamine functionality of the hit series with either an imidazole or a pyrazole ring led to compounds that inhibited both capsid assembly and reverse transcriptase. Optimization of the bicyclic benzodiazepine scaffold to include a 3-phenyl substituent led to lead compound 48, a pure capsid assembly inhibitor with improved antiviral activity.