Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 10, Pages 4369-4385Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00328
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Funding
- Industrial Macromolecular Crystallography Association through a Hauptman-Woodward Medical Research Institute
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
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The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.
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