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.

Non-Nucleoside Reverse Transcriptase Inhibitors: The NNRTI Boom

“…Pyrimidine thioethers (Pharmacia & Upjohn) as inhibitors of HIV-1 RT were first reported by Althaus et al (1996). This class of RT inhibitors is primarily characterised by its potent activity against the P236L mutant, which renders HIV-1 resistant to delavirdine (Nugent et al, 1998).…”

SyGMa: Combining Expert Knowledge and Empirical Scoring in the Prediction of Metabolites

“…[34] The halflife of the compound in microsomal incubation is 11 min. [35] In an effort to increase the metabolic stability, an analogue of this compound has been synthesized in which the N-isopropyl group is replaced by an ethoxy group; it showed an increased half-life of 47 min. [35] In agreement with this observation, Figure 11.…”

“…[35] In an effort to increase the metabolic stability, an analogue of this compound has been synthesized in which the N-isopropyl group is replaced by an ethoxy group; it showed an increased half-life of 47 min. [35] In agreement with this observation, Figure 11. Metabolic pathways of buspirone as summarized by Zhu et al, [30] complemented with two metabolites at the top, indicated by dashed arrows, which were predicted and confirmed experimentally in the present study.…”

Synthesis and Anti-HIV-1 Activity of New Delavirdine Analogues Carrying Arylpyrrole Moieties.

“…The double mutant K103N-Y181C (NIH A17) was derived from a IIIB strain passaged in H9 cells in the presence of Nevirapine as described by Nunberg J. H. et al 16) The HIV-1 wt and the mutant Y181C, K103R and K103N-Y181C stock solutions had titres of 1.0ϫ10 7 (wt) 50% cell culture infectious dose (CCID 50 )/ml, 1.3ϫ10 6 (Y181C) CCID 50 /ml, 3.0ϫ10 5 (K103R) CCID 50 /ml and 2.5ϫ10 5 (Y181C-K103N) CCID 50 /ml, respectively. HIV Titration Virus titration was performed in C8166 cells by the standard limiting dilution method (dilution 1 : 2, four replica wells/dilution) in 96-well plates.…”