Small molecule inhibitors of HIV RT Ribonuclease H

Martin Di Grandi; Matthew Olson; Amar S Prashad; Geraldine Bebernitz; Amara Luckay; Stanley Mullen; Yongbo Hu; Girija Krishnamurthy; Keith Pitts; John O'Connell

doi:10.1016/j.bmcl.2009.10.043

Small molecule inhibitors of HIV RT Ribonuclease H

Bioorg Med Chem Lett. 2010 Jan 1;20(1):398-402. doi: 10.1016/j.bmcl.2009.10.043. Epub 2009 Oct 15.

Authors

Martin Di Grandi¹, Matthew Olson, Amar S Prashad, Geraldine Bebernitz, Amara Luckay, Stanley Mullen, Yongbo Hu, Girija Krishnamurthy, Keith Pitts, John O'Connell

Affiliation

¹ Wyeth Research, 401 North Middletown Road, Pearl River, NY, United States. [email protected]

PMID: 19939680
DOI: 10.1016/j.bmcl.2009.10.043

Abstract

Two classes of compounds, thiocarbamates 1 and triazoles 2, have been identified as HIV RT RNase H inhibitors using a novel FRET-based HTS assay. The potent analogs in each series exhibited selectivity and were active in cell-based assays. In addition, saturable, 1:1 stoichiometric binding to target was established and time of addition studies were consistent with inhibition of RT-mediated HIV replication.

MeSH terms

Amino Acid Sequence
Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry*
Anti-HIV Agents / pharmacology
Cell Line
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Fluorescence Resonance Energy Transfer
High-Throughput Screening Assays
Humans
Molecular Sequence Data
Ribonuclease H, Human Immunodeficiency Virus / antagonists & inhibitors*
Ribonuclease H, Human Immunodeficiency Virus / metabolism
Structure-Activity Relationship
Thiocarbamates / chemical synthesis
Thiocarbamates / chemistry*
Thiocarbamates / pharmacology
Triazoles / chemical synthesis
Triazoles / chemistry*
Triazoles / pharmacology
Virus Replication / drug effects

Substances

Anti-HIV Agents
Enzyme Inhibitors
Thiocarbamates
Triazoles
Ribonuclease H, Human Immunodeficiency Virus