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.
Long-acting
(LA) human immunodeficiency virus-1 (HIV-1) antiretroviral
therapy characterized by a ≥1 month dosing interval offers
significant advantages over daily oral therapy. However, the criteria
for compounds that enter clinical development are high. Exceptional
potency and low plasma clearance are required to meet dose size requirements;
excellent chemical stability and/or crystalline form stability is
required to meet formulation requirements, and new antivirals in HIV-1
therapy need to be largely free of side effects and drug–drug
interactions. In view of these challenges, the discovery that capsid
inhibitors comprising a quinazolinone core tolerate a wide range of
structural modifications while maintaining picomolar potency against
HIV-1 infection in vitro, are assembled efficiently
in a multi-component reaction, and can be isolated in a stereochemically
pure form is reported herein. The detailed characterization of a prototypical
compound, GSK878, is presented, including an X-ray co-crystal structure
and subcutaneous and intramuscular pharmacokinetic data in rats and
dogs.
The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, high human serum shift, and metabolic stability were encountered and overcome through SAR studies. This work culminated in the selection of BMS-986139 () as a preclinical candidate.
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