piperidines and etravirine

A novel series of piperidin-4-yl-aminopyrimidine derivatives were designed fusing the pharmacophore templates of etravirine-VRX-480773 hybrids our group previously described and piperidine-linked aminopyrimidines. Most compounds displayed significantly improved activity against wild-type HIV-1 with EC50 values in single-digit nanomolar concentrations compared to etravirine-VRX-480773 hybrids. Selected compounds were also evaluated for activity against reverse transcriptase, and had lower IC50 values than that of nevirapine. The improved potency observed in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits reverse transcriptase, and represents a remarkable step forward in the development of AIDS therapeutics.

Topics: Anti-HIV Agents; Cells, Cultured; Drug Discovery; HIV Reverse Transcriptase; Humans; Molecular Structure; Nitriles; Piperidines; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclic N-Oxides; Drugs, Investigational; Enfuvirtide; Furans; HIV; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV Integrase Inhibitors; Humans; Nitriles; Oximes; Peptide Fragments; Piperazines; Piperidines; Pyridazines; Pyridines; Pyrimidines; Reverse Transcriptase Inhibitors; Triazoles

Topics: Adenine; Anti-HIV Agents; Clinical Trials as Topic; Cyclic N-Oxides; HIV Infections; Humans; Nitriles; Organophosphonates; Organophosphorus Compounds; Oximes; Piperidines; Pyridazines; Pyridines; Pyrimidines; Tenofovir