Pyridopyrimidinone inhibitors of HIV-1 RNase H

Using a structure based pharmacophore design, a weak inhibitor of RNase H, identified from a small library of two metal binding HIV-1 integrase inhibitors, was optimized for potency and physicochemical properties. This manuscript describes the SAR and in vivo DMPK for the pyridopyrimidinone class of...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2014-08, Vol.83, p.609-616
Main Authors: Velthuisen, Emile J., Johns, Brian A., Gerondelis, Peter, Chen, Yan, Li, Ming, Mou, Ke, Zhang, Wenwen, Seal, John W., Hightower, Kendra E., Miranda, Sonia R., Brown, Kevin, Leesnitzer, Lisa
Format: Article
Language:English
Subjects:
AIDS
Animals
Endonuclease
HIV
HIV-1 - enzymology
Integrase
Male
Pyrimidinones - chemistry
Pyrimidinones - pharmacokinetics
Pyrimidinones - pharmacology
Rats
Rats, Sprague-Dawley
Reverse transcriptase
Reverse Transcriptase Inhibitors - chemistry
Reverse Transcriptase Inhibitors - pharmacokinetics
Reverse Transcriptase Inhibitors - pharmacology
Ribonuclease H, Human Immunodeficiency Virus - antagonists & inhibitors
Structure-Activity Relationship
Two-metal binder
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Summary:Using a structure based pharmacophore design, a weak inhibitor of RNase H, identified from a small library of two metal binding HIV-1 integrase inhibitors, was optimized for potency and physicochemical properties. This manuscript describes the SAR and in vivo DMPK for the pyridopyrimidinone class of inhibitors. [Display omitted] •Screening identified several naphthyridines as weak inhibitors of RT strand transfer.•A pyridopyrimidinone pharmacophore was subsequently designed as a potent inhibitor of HIV-1 RNase H catalytic activity.•SAR optimization focused on both potency and physicochemical properties.•Rat in vivo studies demonstrated poor bioavailability likely attributed to low cell permeability.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2014.06.061