title: (Alkylamino) piperidine bis(heteroaryl)piperizine analogs are potent, broad-spectrum nonnucleoside reverse transcriptase inhibitors of drug-resistant isolates of human immunodeficiency virus type 1 (HIV-1) and select for drug-resistant variants of HIV-1IIIB with reduced replication phenotypes.
abstract: The (alkylamino)piperidine bis(heteroaryl)piperizines (AAP-BHAPs) are a new class of human immunodeficiency virus type 1 (HIV-1)-specific inhibitors which were identified by targeted screening of recombinant reverse transcriptase (RT) enzymes carrying key nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-conferring mutations and NNRTI-resistant variants of HIV-1. Phenotypic profiling of the two most potent AAP-BHAPs, U-95133 and U-104489, against in vitro-selected drug-resistant HIV-1 variants carrying the NNRTI resistance-conferring mutation (Tyr->Cys) at position 181 of the HIV-1 RT revealed submicromolar 90% inhibitory concentration estimates for these compounds. Moreover, U-104489 demonstrated potent activity against BHA-P-resistant HIV-1MF harboring the Pro-236->Leu RT substitution and significantly suppressed the replication of clinical isolates of HIV-1 resistant to both delavirdine (BHAP U-90152T) and zidovudine. Biochemical and phenotypic characterization of AAP-BHAPresistant HIV-1IIIB variants revealed that high-level resistance to the AAP-BHAPs was mediated by a Gly-190->Glu substitution in RT, which had a deleterious effect on the integrity and enzymatic activity of virion-associated RT heterodimers, as well as the replication capacity of these resistant viruses.
authors.affiliation: Cancer and Infectious Diseases Research, Pharmacia & Upjohn, Kalamazoo, Michigan 49001.
authors.forename: R A
authors.initials: RA
authors.lastname: Olmsted
authors.forename: D E
authors.initials: DE
authors.lastname: Slade
authors.forename: L A
authors.initials: LA
authors.lastname: Kopta
authors.forename: S M
authors.initials: SM
authors.lastname: Poppe
authors.forename: T J
authors.initials: TJ
authors.lastname: Poel
authors.forename: S W
authors.initials: SW
authors.lastname: Newport
authors.forename: K B
authors.initials: KB
authors.lastname: Rank
authors.forename: C
authors.initials: C
authors.lastname: Biles
authors.forename: R A
authors.initials: RA
authors.lastname: Morge
authors.forename: T J
authors.initials: TJ
authors.lastname: Dueweke
authors.forename: Y
authors.initials: Y
authors.lastname: Yagi
authors.forename: D L
authors.initials: DL
authors.lastname: Romero
authors.forename: R C
authors.initials: RC
authors.lastname: Thomas
authors.forename: S K
authors.initials: SK
authors.lastname: Sharma
authors.forename: W G
authors.initials: WG
authors.lastname: Tarpley
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D004351:Drug Resistance; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase