title: 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.
abstract: 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.
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: Sylvie
authors.initials: S
authors.lastname: Goulet
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: Isabelle
authors.initials: I
authors.lastname: Dion
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: Jean
authors.initials: J
authors.lastname: Rancourt
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonneau
authors.forename: Steve
authors.initials: S
authors.lastname: Titolo
authors.forename: Ma'an
authors.initials: M
authors.lastname: Amad
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
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; D001570:Benzodiazepinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018938:Caco-2 Cells; D036022:Capsid Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D018360:Crystallography, X-Ray; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019065:Virus Assembly / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D001570:Benzodiazepinones; D036022:Capsid Proteins; D001569:Benzodiazepines