title: Discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly.
abstract: 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.
authors.affiliation: Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, Que, Canada. lee.fader@boehringer-ingelheim.com
authors.forename: Lee D
authors.initials: LD
authors.lastname: Fader
authors.forename: Richard
authors.initials: R
authors.lastname: Bethell
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonneau
authors.forename: Michael
authors.initials: M
authors.lastname: Bös
authors.forename: Yves
authors.initials: Y
authors.lastname: Bousquet
authors.forename: Michael G
authors.initials: MG
authors.lastname: Cordingley
authors.forename: René
authors.initials: R
authors.lastname: Coulombe
authors.forename: Patrick
authors.initials: P
authors.lastname: Deroy
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Faucher
authors.forename: Alexandre
authors.initials: A
authors.lastname: Gagnon
authors.forename: Nathalie
authors.initials: N
authors.lastname: Goudreau
authors.forename: Chantal
authors.initials: C
authors.lastname: Grand-Maître
authors.forename: Ingrid
authors.initials: I
authors.lastname: Guse
authors.forename: Oliver
authors.initials: O
authors.lastname: Hucke
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Kawai
authors.forename: Jean-Eric
authors.initials: JE
authors.lastname: Lacoste
authors.forename: Serge
authors.initials: S
authors.lastname: Landry
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Lemke
authors.forename: Eric
authors.initials: E
authors.lastname: Malenfant
authors.forename: Stephen
authors.initials: S
authors.lastname: Mason
authors.forename: Sébastien
authors.initials: S
authors.lastname: Morin
authors.forename: Jeff
authors.initials: J
authors.lastname: O'Meara
authors.forename: Bruno
authors.initials: B
authors.lastname: Simoneau
authors.forename: Steve
authors.initials: S
authors.lastname: Titolo
authors.forename: Christiane
authors.initials: C
authors.lastname: Yoakim
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D036022:Capsid Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D001570:Benzodiazepinones; D036022:Capsid Proteins; D007093:Imidazoles; D011720:Pyrazoles; D018894:Reverse Transcriptase Inhibitors; C031280:pyrazole; C029899:imidazole; D054303:HIV Reverse Transcriptase