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

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.

A review on HCV inhibitors: Significance of non-structural polyproteins

“…[86]. Additionally, the replacement of oxazinoindole of MK-8876 with linear aryl rings provided BMS-929075 as pan HCV NS5B inhibitor (171, 1a & 1b, EC 50¼ 9 & 4 nM) as clinical candidate with improvised oral bioavailability and pharmacokinetics [87]. The benzofurone clinical investigative HCV NS5B candidates were shown in Fig.…”

A Novel Small Molecule Inhibits Hepatitis C Virus Propagation in Cell Culture

“…Interestingly, AO13 showed two potential hydrogen bonds at Tyr 448 and Cys 366, which were reported to be the most important residues in the active site cavity within the palm allosteric site of the NS5B polymerase ( 28 , 29 ). AO13 fitted well into the allosteric binding pocket with another hydrogen bond between the sulfur atom and Tyr 415.…”

“…Investigating the binding mode of AO13 indicated a π-π stacking with Phe 193, which would enhance the stabilization of the compound in the allosteric site. Binding of AO13 to important residues within the palm I region, i.e., Tyr 448, Cys 366, and Tyr 415, predicts that the compound could potentially act as an HCV NS5B polymerase inhibitor ( 28 , 29 ). It is important to note here that these residues are conserved within multiple crystal structures of NS5B ( 35 , 36 ).…”

Development of a New Structural Class of Broadly Acting HCV Non‐Nucleoside Inhibitors Leading to the Discovery of MK‐8876

“…Based on these potency data we set out to develop compounds that would inhibit HCV NS5B by binding the palm II site while retaining potent activity against all of the clinically relevant major genotypes. Similar strategies conducted in parallel to this work have recently been described …”