title: Targeting delavirdine/atevirdine resistant HIV-1: identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors.
abstract: A novel class of bis(heteroaryl)piperazine (BHAP) analogs which possesses the ability to inhibit NNRTI (non-nucleoside reverse transcriptase inhibitor) resistant recombinant HIV-1 reverse transcriptase (RT) and NNRTI resistant variants of HIV-1 has been identified via targeted screening. Further investigation of the structure-activity relationships of close congeners of these novel (alkylamino)piperidine BHAPs (AAP-BHAPs) led to the synthesis of several compounds possessing the desired phenotype (e.g., activity against recombinant RTs carrying the Y181C and P236L substitutions). Further structural modifications were required to inhibit metabolism and modulate solubility in order to obtain compounds with the desired biological profile as well as appropriate pharmaceutical properties. The AAP-BHAPs with the most suitable characteristics were compounds 7, 15, and 36.
authors.affiliation: DDR&D Pharmaceutics, Pharmacia & Upjohn, Inc, Kalamazoo, Michigan 49001, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Romero
authors.forename: R A
authors.initials: RA
authors.lastname: Olmsted
authors.forename: T J
authors.initials: TJ
authors.lastname: Poel
authors.forename: R A
authors.initials: RA
authors.lastname: Morge
authors.forename: C
authors.initials: C
authors.lastname: Biles
authors.forename: B J
authors.initials: BJ
authors.lastname: Keiser
authors.forename: L A
authors.initials: LA
authors.lastname: Kopta
authors.forename: J M
authors.initials: JM
authors.lastname: Friis
authors.forename: J D
authors.initials: JD
authors.lastname: Hosley
authors.forename: K J
authors.initials: KJ
authors.lastname: Stefanski
authors.forename: D G
authors.initials: DG
authors.lastname: Wishka
authors.forename: D B
authors.initials: DB
authors.lastname: Evans
authors.forename: J
authors.initials: J
authors.lastname: Morris
authors.forename: R G
authors.initials: RG
authors.lastname: Stehle
authors.forename: S K
authors.initials: SK
authors.lastname: Sharma
authors.forename: Y
authors.initials: Y
authors.lastname: Yagi
authors.forename: R L
authors.initials: RL
authors.lastname: Voorman
authors.forename: W J
authors.initials: WJ
authors.lastname: Adams
authors.forename: W G
authors.initials: WG
authors.lastname: Tarpley
authors.forename: R C
authors.initials: RC
authors.lastname: Thomas
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D020008:Delavirdine; D004352:Drug Resistance, Microbial; D004355:Drug Stability; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology*; D015394:Molecular Structure; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C101614:1-((5-(((4-methyl-1-piperazinyl)carbonyl)amino)indol-2-yl)carbonyl)-4-(N-ethyl-N-(3-((1,1-dimethylethyl)amino)-6-fluoro-2-pyridinyl)amino)piperidine; C101612:1-((5-methanesulfonamidoindol-2-yl)carbonyl)-4-(N-methyl-N-(3-((1,1-dimethylethyl)amino)-2-pyridinyl)amino)piperidine; C101613:1-((5-methanesulfonamidoindol-2-yl-)carbonyl)-4-(N-ethyl-N-(3-((1,1-dimethylethyl)amino)-2-pyridinyl)amino)piperidine; D019380:Anti-HIV Agents; D007211:Indoles; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D020008:Delavirdine; D054303:HIV Reverse Transcriptase; C076632:atevirdine