title: 'Double-Drugs'--a new class of prodrug form of an HIV protease inhibitor conjugated with a reverse transcriptase inhibitor by a spontaneously cleavable linker.
abstract: We designed and synthesized a new series of prodrug-type anti-HIV agents consisting of a peptidomimetic HIV protease inhibitor conjugated with a nucleoside reverse transcriptase inhibitor in an effort to enhance the antiviral activity. For the conjugation, a series of linkers that conjoin the two different classes of inhibitors have been investigated. Conjugates using a succinyl amino acid linker were shown to release the parent components via the spontaneous imide formation at a faster rate compared to conjugates using a glutaryl amino acid linker, as expected from the energetically favorable cyclization to the five-membered ring. Herein, we report a new 'double-drug' 4b (KNI-1039) with a glutarylglycine linker, which exhibited extremely potent anti-HIV activity compared with that of the individual components.
authors.affiliation: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Matsumoto
authors.forename: T
authors.initials: T
authors.lastname: Hamawaki
authors.forename: H
authors.initials: H
authors.lastname: Ota
authors.forename: T
authors.initials: T
authors.lastname: Kimura
authors.forename: T
authors.initials: T
authors.lastname: Goto
authors.forename: K
authors.initials: K
authors.lastname: Sano
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry*; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; C414944:KNI 1039; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles; D015215:Zidovudine