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J Med Chem. 2017 Mar 23;60(6):2305-2325. doi: 10.1021/acs.jmedchem.6b01568. Epub 2017 Mar 13.

Identification of Non-Nucleoside Inhibitors of the Respiratory Syncytial Virus Polymerase Complex.

Author information

1
Emory Institute for Drug Development, Emory University , Atlanta, Georgia 30329, United States.
2
Institute for Biomedical Sciences, Georgia State University , Atlanta, Georgia 30303, United States.
3
Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.

Abstract

Respiratory syncytial virus (RSV) represents a threat to infants, the elderly, and the immunocompromised. RSV entry blockers are in clinical trials, but escape mutations challenge their potential. In search of RSV inhibitors, we have integrated a signature resistance mutation into a recombinant RSV virus and applied the strain to high-throughput screening. Counterscreening of candidates returned 14 confirmed hits with activities in the nano- to low-micromolar range. All blocked RSV polymerase activity in minigenome assays. Compound 1a (GRP-74915) was selected for development based on activity (EC50 = 0.21 μM, selectivity index (SI) 40) and scaffold. Resynthesis confirmed the potency of the compound, which suppressed viral RNA synthesis in infected cells. However, metabolic testing revealed a short half-life in the presence of mouse hepatocyte fractions. Metabolite tracking and chemical elaboration combined with 3D-quantitative structure-activity relationship modeling yielded analogues (i.e., 8n: EC50 = 0.06 μM, SI 500) that establish a platform for the development of a therapeutic candidate.

PMID:
28245119
PMCID:
PMC5504085
DOI:
10.1021/acs.jmedchem.6b01568
[Indexed for MEDLINE]
Free PMC Article

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