Synthesis and structure-activity relationships of the (alkylamino)piperidine-containing BHAP class of non-nucleoside reverse transcriptase inhibitors: Effect of 3-alkylpyridine ring substitution

Development of resistance to currently approved HIV therapies has continued to fuel research efforts to improve the metabolic stability and spectrum o f activity of the (alkyl amino)piperidine containing bis(heteroaryl)piperaz ine (AAP-BHAP) class of non-nucleoside reverse transcriptase inhibitors (NN RTIs). The synthesis of analogues in which the usual 3-alkylamino substitue nt on the pyridine ring is replaced by a 3-alkyl substituent led to compoun ds which retained activity against recombinant P236L and wild-type (WT) rev erse transcriptase (RT), while inhibition of the Y181C mutant RT was reduce d relative to the activity of the 3-alkylamino-substituted congeners. Testi ng of representative analogues in an in vitro liver microsome assay indicat ed that the alkyl substituent would not appreciably improve the metabolic s tability of the AAP-BHAP template. In vivo pharmacokinetic evaluation of th ree compounds confirmed these results in that high systemic clearances were observed. Nevertheless, one compound (13), PNU-103657, possessed oral bioa vailability in rats approaching that of the structurally related NNRTI drug delavirdine which is currently on the market for the treatment of HIV infe ction.