title: Synthesis and bioactivity of novel bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: structure-activity relationships and increased metabolic stability of novel substituted pyridine analogs.
abstract: The major route of metabolism of the bis(heteroaryl)piperazine (BHAP) class of reverse transcriptase inhibitors (RTIs), atevirdine and delavirdine, is via oxidative N-dealkylation of the 3-ethyl- or 3-isopropylamino substituent on the pyridine ring. This metabolic pathway is also the predominant mode of metabolism of (alkylamino)piperidine BHAP analogs (AAP-BHAPs), compounds wherein a 4-(alkylamino)piperidine replaces the piperazine ring of the BHAPs. The novel AAP-BHAPs possess the ability to inhibit non-nucleoside reverse transcriptase inhibitor (NNRTI) resistant recombinant HIV-1 RT and NNRTI resistant variants of HIV-1. This report describes an approach to preventing this degradation which involves the replacement of the 3-ethyl- or 3-isopropylamino substituent with either a 3-tert-butylamino substituent or a 3-alkoxy substituent. The synthesis, bioactivity and metabolic stability of these analogs is described. The majority of analogs retain inhibitory activities in enzyme and cell culture assays. In general, a 3-ethoxy or 3-isopropoxy substituent on the pyridine ring, as in compounds 10, 20, or 21, resulted in enhanced stabilities. The 3-tert-butylamino substituent was somewhat beneficial in the AAP-BHAP series of analogs, but did not exert a significant effect in the BHAP series. Lastly, the nature of the indole substitution sometimes plays a significant role in metabolic stability, particularly in the BHAP series of analogs.
authors.affiliation: Pharmacia & Upjohn, Kalamazoo, Michigan 49001, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Genin
authors.forename: T J
authors.initials: TJ
authors.lastname: Poel
authors.forename: Y
authors.initials: Y
authors.lastname: Yagi
authors.forename: C
authors.initials: C
authors.lastname: Biles
authors.forename: I
authors.initials: I
authors.lastname: Althaus
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: F
authors.initials: F
authors.lastname: Reusser
authors.forename: W J
authors.initials: WJ
authors.lastname: Adams
authors.forename: R A
authors.initials: RA
authors.lastname: Olmsted
authors.forename: R L
authors.initials: RL
authors.lastname: Voorman
authors.forename: R C
authors.initials: RC
authors.lastname: Thomas
authors.forename: D L
authors.initials: DL
authors.lastname: Romero
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D010879:Piperazines; D018894:Reverse Transcriptase Inhibitors; D003577:Cytochrome P-450 Enzyme System