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J Med Chem. 2017 May 25;60(10):4369-4385. doi: 10.1021/acs.jmedchem.7b00328. Epub 2017 May 4.

Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies.

Author information

1
Bristol-Myers Squibb Research and Development , P.O. Box 5100, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
2
Department of Discovery Chemistry, Biocon Bristol-Myers Squibb Research and Development Center , Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560099, India.
3
Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
4
Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08901, United States.

Abstract

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.

PMID:
28430437
DOI:
10.1021/acs.jmedchem.7b00328
[Indexed for MEDLINE]

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