SYNTHESIS AND BIOACTIVITY OF NOVEL BIS (HETEROARYL)PIPERAZINE (BHAP) REVERSE-TRANSCRIPTASE INHIBITORS - STRUCTURE-ACTIVITY-RELATIONSHIPS AND INCREASED METABOLIC STABILITY OF NOVEL SUBSTITUTED PYRIDINE ANALOGS

The major route of metabolism of the bis(heteroaryl)piperazine (BHAP) class of reverse transcriptase inhibitors (RTIs), atevirdine and delav irdine, is via oxidative N-dealkylation of the 3-ethyl- or 3-isopropyl amino substituent on the pyridine ring. This metabolic pathway is also the predominant mode of metabolism of (alkylamino)piperidine BHAP ana logs (AAP-BHAPs), compounds wherein a 4-(alkylamino)piperidine replace s the piperazine ring of the BHAPs. The novel AAP-BHAPs possess the ab ility 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 whi ch involves the replacement of the 3-ethyl- or 3-isopropylamino substi tuent with either a 3-tert-butylamino substituent or a 3-alkoxy substi tuent. The synthesis, bioactivity and metabolic stability of these ana logs is described. The majority of analogs retain inhibitory activitie s in enzyme and cell culture assays. In general, a 3-ethoxy or 3-isopr opoxy substituent on the pyridine ring, as in compounds 10, 20, or 21, resulted in enhanced stabilities. The 3-tert-butylamino substituent w as somewhat beneficial in the AAP-BHAP series of analogs, but did not exert a significant effect in the BHAP series. Lastly, the nature of t he indole substitution sometimes plays a significant role in metabolic stability, particularly in the BHAP series of analogs.