Synthesis and evaluation of 2-pyridinone derivatives as specific HIV-1 reverse transcriptase inhibitors. 3. Pyridyl and phenyl analogs of 3-aminopyridin-2(1H)-one

Abstract

In an ongoing effort to develop novel nonnucleoside, specific human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitors, a series of 3-[(pyridylmethyl)amino]- and 3-[(phenylmethyl)amino]-2-pyridinone derivatives was synthesized and tested for HIV-1 RT inhibitory activity. The more potent compounds have a 2'-methoxy group and 4'- and/or 5'-aliphatic substituents on the pyridyl and phenyl rings. Several of the more potent compounds were also evaluated for antiviral activity in MT-4 cell culture. From this series of compounds, 3-[N-[(5-ethyl-2-methoxy-6-methyl-3-pyridyl)methyl]amino]-5-ethyl-6- methylpyridin-2(1H)-one (6) was selected for clinical evaluation.

Non-Nucleoside Reverse Transcriptase Inhibitors: The NNRTI Boom

“…These include N-methylation, O-methylation, deletion of one or both alkyl groups and substituting 5-ethyl with 5-methyl. Some structure-activity studies have also been done replacing the benzoxazole by a pyridyl or a phenyl (Wai et al, 1993) (Table 24). It was found that maximum enzyme inhibition was obtained with compounds containing a 2′-methoxy group on either the phenyl or pyridyl ring.…”

“…†Concentration of compound that inhibits the spread of HIV-1 infection in MT-4 cells, by ≥95% using a p24 core antigen ELISA assay. Data from Wai et al (1993). *The concentration that produced 50% inhibition of RT using a rC.dG template primer, and stated as the mean of at least three determinations ±SEM.…”

Development of pharmacophore models for predicting HIV-1 reverse transcriptase inhibitory activity of pyridinone derivatives

“…In vitro biological data for a series of 38 pyridinone derivatives [8] having HIV-1 RT inhibitory activity was used for the present studies. These derivatives were evaluated for inhibiting the spread of HIV-1 infection in MT-4 cell culture [8].…”

“…These derivatives were evaluated for inhibiting the spread of HIV-1 infection in MT-4 cell culture [8]. The HIV-RT inhibitory activity was expressed as pIC 50 .…”

Pyridin‐2(1H)‐ones: A Promising Class of HIV‐1 Non‐nucleoside Reverse Transcriptase Inhibitors

“…[26] Binding Mode into the NNRTIs Binding Pocket Automated docking and 3D-QSAR of Merck pyridinones As mentioned earlier, biological experiments showed that A C H T U N G T R E N N U N G L-697,661, L-697,639, L-696,229, and other related Merck pyridinones should bind in the NNRTIs pocket. Several two-dimensional quantitative structure-activity relationship analyses (2D-QSAR) have been performed for this subtype of pyridinone analogue, [9,11,12,29] suggesting a hydrophobic character of their binding site. [30,31] However, no crystal structures of HIV-1 RT in complex with Merck pyridinones are available.…”