Pyridopyrimidinone inhibitors of HIV-1 RNase H

Emile J Velthuisen; Brian A Johns; Peter Gerondelis; Yan Chen; Ming Li; Ke Mou; Wenwen Zhang; John W Seal; Kendra E Hightower; Sonia R Miranda; Kevin Brown; Lisa Leesnitzer

doi:10.1016/j.ejmech.2014.06.061

Pyridopyrimidinone inhibitors of HIV-1 RNase H

Eur J Med Chem. 2014 Aug 18:83:609-16. doi: 10.1016/j.ejmech.2014.06.061. Epub 2014 Jun 28.

Authors

Affiliations

¹ GlaxoSmithKline Research & Development, Infectious Diseases Therapeutic Area Unit, Five Moore Drive, Research Triangle Park, NC 27709, United States. Electronic address: emile.j.velthuisen@gsk.com.
² GlaxoSmithKline Research & Development, Infectious Diseases Therapeutic Area Unit, Five Moore Drive, Research Triangle Park, NC 27709, United States.

PMID: 24997293
DOI: 10.1016/j.ejmech.2014.06.061

Abstract

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.

Keywords: AIDS; Endonuclease; HIV; Integrase; Reverse transcriptase; Two-metal binder.

MeSH terms

Animals
HIV-1 / enzymology*
Male
Pyrimidinones / chemistry*
Pyrimidinones / pharmacokinetics
Pyrimidinones / pharmacology*
Rats
Rats, Sprague-Dawley
Reverse Transcriptase Inhibitors / chemistry*
Reverse Transcriptase Inhibitors / pharmacokinetics
Reverse Transcriptase Inhibitors / pharmacology*
Ribonuclease H, Human Immunodeficiency Virus / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Pyrimidinones
Reverse Transcriptase Inhibitors
Ribonuclease H, Human Immunodeficiency Virus