title: Optimization of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of HIV capsid assembly inhibitors 1: addressing configurational instability through scaffold modification.
abstract: The optimization of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly that possess a labile stereocenter at C3 is described. Quaternization of the C3 position of compound 1 in order to prevent racemization gave compound 2, which was inactive in our capsid disassembly assay. A likely explanation for this finding was revealed by in silico analysis predicting a dramatic increase in energy of the bioactive conformation upon quaternization of the C3 position. Replacement of the C3 of the diazepine ring with a nitrogen atom to give the 1,5-dihydro-benzo[f][1,3,5]triazepine-2,4-dione analog 4 was well tolerated. Introduction of a rigid spirocyclic system at the C3 position gave configurationally stable 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione analog 5, which was able to access the bioactive conformation without a severe energetic penalty and inhibit capsid assembly. Preliminary structure-activity relationships (SAR) and X-ray crystallographic data show that knowledge from the 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly can be transferred to these new scaffolds.
authors.affiliation: Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5. lee.fader@boehringer-ingelheim.com
authors.forename: Lee D
authors.initials: LD
authors.lastname: Fader
authors.forename: Serge
authors.initials: S
authors.lastname: Landry
authors.forename: Sébastien
authors.initials: S
authors.lastname: Morin
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Kawai
authors.forename: Yves
authors.initials: Y
authors.lastname: Bousquet
authors.forename: Oliver
authors.initials: O
authors.lastname: Hucke
authors.forename: Nathalie
authors.initials: N
authors.lastname: Goudreau
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Lemke
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonneau
authors.forename: Steve
authors.initials: S
authors.lastname: Titolo
authors.forename: Stephen
authors.initials: S
authors.lastname: Mason
authors.forename: Bruno
authors.initials: B
authors.lastname: Simoneau
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D036022:Capsid Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019065:Virus Assembly / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D036022:Capsid Proteins; D001569:Benzodiazepines