title: Nucleotide competing reverse transcriptase inhibitors: discovery of a series of non-basic benzofurano[3,2-d]pyrimidin-2-one derived inhibitors.
abstract: A HTS screen led to the identification of a benzofurano[3,2-d]pyrimidin-2-one core structure which upon further optimization resulted in 1 as a potent HIV-1 nucleotide competing reverse transcriptase inhibitor (NcRTI). Investigation of the SAR at N-1 allowed significant improvements in potency and when combined with the incorporation of heterocycles at C-8 resulted in potent analogues not requiring a basic amine to achieve antiviral activity. Additional modifications at N-1 resulted in 33 which demonstrated excellent antiviral potency and improved physicochemical properties.
authors.affiliation: Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5. clint.james@boehringer-ingelheim.com
authors.forename: Clint A
authors.initials: CA
authors.lastname: James
authors.forename: Patrick
authors.initials: P
authors.lastname: DeRoy
authors.forename: Martin
authors.initials: M
authors.lastname: Duplessis
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Edwards
authors.forename: Teddy
authors.initials: T
authors.lastname: Halmos
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: Bruno
authors.initials: B
authors.lastname: Simoneau
authors.forename: Martin
authors.initials: M
authors.lastname: Tremblay
authors.forename: Richard
authors.initials: R
authors.lastname: Bethell
authors.forename: Michael
authors.initials: M
authors.lastname: Cordingley
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
authors.forename: Louie
authors.initials: L
authors.lastname: Lamorte
authors.forename: Alex
authors.initials: A
authors.lastname: Pelletier
authors.forename: Daniel
authors.initials: D
authors.lastname: Rajotte
authors.forename: Patrick
authors.initials: P
authors.lastname: Salois
authors.forename: Sonia
authors.initials: S
authors.lastname: Tremblay
authors.forename: Claudio F
authors.initials: CF
authors.lastname: Sturino
mesh_terms: D001572:Benzofurans / Q000737:chemistry*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; 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; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; 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