title: Identification of benzofurano[3,2-d]pyrimidin-2-ones, a new series of HIV-1 nucleotide-competing reverse transcriptase inhibitors.
abstract: Screening of our sample collection led to the identification of a set of benzofurano[3,2-d]pyrimidine-2-one hits acting as nucleotide-competing HIV-1 reverse transcriptase inhibitiors (NcRTI). Significant improvement in antiviral potency was achieved when substituents were introduced at positions N1, C4, C7 and C8 on the benzofuranopyrimidone scaffold. The series was optimized from low micromolar enzymatic activity against HIV-1 RT and no antiviral activity to low nanomolar antiviral potency. Further profiling of inhibitor 30 showed promising overall in vitro properties and also demonstrated that its potency was maintained against viruses resistant to the other major classes of HIV-1 RT inhibitors.
authors.affiliation: Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5. martin.tremblay@boehringer-ingelheim.com
authors.forename: Martin
authors.initials: M
authors.lastname: Tremblay
authors.forename: Richard C
authors.initials: RC
authors.lastname: Bethell
authors.forename: Michael G
authors.initials: MG
authors.lastname: Cordingley
authors.forename: Patrick
authors.initials: P
authors.lastname: DeRoy
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
authors.forename: Martin
authors.initials: M
authors.lastname: Duplessis
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Edwards
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Faucher
authors.forename: Ted
authors.initials: T
authors.lastname: Halmos
authors.forename: Clint A
authors.initials: CA
authors.lastname: James
authors.forename: Cyrille
authors.initials: C
authors.lastname: Kuhn
authors.forename: Jean-Éric
authors.initials: JÉ
authors.lastname: Lacoste
authors.forename: Louie
authors.initials: L
authors.lastname: Lamorte
authors.forename: Steven R
authors.initials: SR
authors.lastname: LaPlante
authors.forename: Eric
authors.initials: E
authors.lastname: Malenfant
authors.forename: Joannie
authors.initials: J
authors.lastname: Minville
authors.forename: Louis
authors.initials: L
authors.lastname: Morency
authors.forename: Sébastien
authors.initials: S
authors.lastname: Morin
authors.forename: Daniel
authors.initials: D
authors.lastname: Rajotte
authors.forename: Patrick
authors.initials: P
authors.lastname: Salois
authors.forename: Bruno
authors.initials: B
authors.lastname: Simoneau
authors.forename: Sonia
authors.initials: S
authors.lastname: Tremblay
authors.forename: Claudio F
authors.initials: CF
authors.lastname: Sturino
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D009711:Nucleotides; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C105430:benzofuran