Discovery of Narlaprevir (SCH 900518): A Potent, Second Generation HCV NS3 Serine Protease Inhibitor

Abstract

Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (∼10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.KEYWORDS Hepatitis C virus NS3 serine protease inhibitor, R-ketoamide, narlaprevir, SCH 900518 H epatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma and liver failure in humans. 1 An estimated 3% of the human population worldwide is chronically infected with HCV. 2 Currently the only available treatment regimens are subcutaneous R-interferon or long-acting pegylated-interferon, alone or in combination with oral antiviral agent ribavirin. 3 The approved therapy is still far from ideal for the hard to treat genotype-1 patients 4 and is frequently accompanied by adverse side effects. There is an unmet medical need to discover new, more effective and tolerable regimens for the treatment of HCV infection. Advances in the understanding of molecular pathways of HCV replication have resulted in several small molecule direct-acting antivirals entering clinical trials in the past few years.Since identification of this virus, the NS3 serine protease contained within the N-terminal region of the NS3 protein has been studied extensively. 5 This chymotrypsin-like serine protease plays a pivotal role in viral replication and, therefore, is an attractive target for HCV antiviral therapeutics. 6,7 Intense efforts were focused in the past decade to discover novel small molecule agents that inhibit NS3 serine protease. 8 Proof of concept studies in humans with BILN 2061, a noncovalent P1-P3 macrocyclic inhibitor, validated this hypothesis. 9 Since then, several NS3 protease inhibitors have progressed to human clinical trials. Currently the most advanced among those are boceprevir (SCH 503034), 1, 10,11 and telaprevir (VX950), 12,13 from the slow-binding reversible R-ketoamide class, in phase III human evaluation. Inhibitors in phase II studies, from the structurally distinct noncovalent macrocyclic class, include 14 15 and MK-7009 (P2-P4 macrocycle). 16 Other NS3 protease inhibitors currently in clinical evaluation (structure not yet disclosed) include BI-201335, ABT-450, PHX-1766, ACH-1625 and VX-813. 8 Inhibitor 1 exhibited K i * = 14 nM in the enzyme binding assay, 17 EC 90 = 350 nM in the cell-based replicon assay, 18 and acceptable pharmacokinetic profile in rats and dogs (Figure 1). In our efforts to discover a second generation HCV protease inhibitor, we focused mainly on improving the in vitro potency and preclinical pharmacokinetic profile of the inhibitor, specifically exposure in monkeys. Further...

Preclinical Characterization of the Antiviral Activity of SCH 900518 (Narlaprevir), a Novel Mechanism-Based Inhibitor of Hepatitis C Virus NS3 Protease

“…Of note, replicon cells resistant to SCH 900518 remained sensitive to interferon alfa-2b. X-ray structural analysis (1) showed that the A156 side chain is in van der Waals contact with the P2 and P4 side chains of SCH 900518. Mutation of A156 to bulkier residues (Ser/Thr/Val) causes stereo hindrance in the region.…”

“…The crystal structure of SCH 900518 complexed with the NS3-NS4A protease was solved in-house (1). To illustrate the key resistance-conferring loci, the structure of SCH 900518 is presented as a stick model, and the side chains of residues are shown by using CPK models on the Connolly surface of the NS3 protease.…”

Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease

“…27–35 However, despite potent activity against wild-type GT-1, PIs suffer from a low genetic barrier to resistance. 36 We have previously described the molecular basis for resistance to many of these inhibitors in terms of the substrate envelope and macrocyclization.…”

Proteases and protease inhibitors in infectious diseases

“…Developed as all‐oral once daily dosing, these would need to be co‐administered with other DAAs in order to overcome resistance barriers. Their SARs as collated during the process of discovery have also been made public . Across the board, structural modification of P 2 residues in particular produced remarkable improvement in potency as well as safety.…”