Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates

Abstract

Lomibuvir (1) is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy. Further development efforts within this class of inhibitor focused on improving the antiviral activity and physicochemical and pharmacokinetic properties. Recently, we reported the development of this series, leading to compound 2, a molecule with comparable potency and an improved physicochemical profile relative to 1. Further exploration of the amino amide-derived side chain led to a series of lactam derivatives, inspired by the X-ray crystal structure of related thiophene carboxylate inhibitors. This series, exemplified by 12f, provided 3−5-fold improvement in potency against HCV replication, as measured by replicon assays. The synthesis, structure−activity relationships, in vitro ADME characterization, and in vivo evaluation of this novel series are discussed. KEYWORDS: Lomibuvir, non-nucleoside, hepatitis C, NS5B, polymerase, antiviral activity H epatitis C virus (HCV) infects an estimated 80−115 million people worldwide. 1 Chronic infection is associated with increased risk of liver disease, fibrosis and cirrhosis, and hepatocellular carcinoma. 2 In 2011, the HCV NS3 protease inhibitors boceprevir 3 and telaprevir 4 were approved as the first direct-acting antiviral agents, administered in combination with pegylated interferon α and ribavirin. 5 In the following years, more efficacious agents and combinations have been introduced, and these two protease inhibitor drugs have been superseded. 6,7 In our quest for new chemical agents needed to decrease the duration of treatment and reduce treatment side effects, we focused on developing inhibitors of the NS5B polymerase, an approach anticipated to deliver an alloral, interferon-free treatment regimen when applied in combination with telaprevir. The viral NS5B polymerase plays an essential role in the life cycle of HCV, being responsible for viral genomic replication. 8 Inhibitors of this enzyme in clinical development and practice fall into two classes: nucleoside (or nucleotide) analogues and non-nucleoside, allosteric inhibitors. 9 Lomibuvir (1: also named VX-222 and VCH-222) is a selective, non-nucleoside polymerase inhibitor that binds to thumb pocket 2 of the HCV NS5B polymerase. 10 A 3-day, monotherapy viral kinetic study in which treatment-naïve patients with genotype 1 HCV infection were treated with 250, 500, or 750 mg lomibuvir twice daily, or 1500 mg once daily, showed it to be well tolerated, and patients achieved a mean HCV RNA reduction ranging from 3.1 to 3.4 log 10 . 11 To continue to develop this series, our program focused on improving physicochemical and pharmacokinetic properties. As we recently reported, replacement of the trans-4-hydroxycyclohexane ring in 1 with a glycine-derived amide (2) resulted in comparable potency and improved physicochemical properties. 12 During the course of this work, we established that although compounds such as 3b showed higher activity than the corresponding R-ena...

Designing Out PXR Activity on Drug Discovery Projects: A Review of Structure-Based Methods, Empirical and Computational Approaches

“…More recently BMS have disclosed their efforts to mitigate undesired PXR activity in one of their series of 11β-HSD1 inhibitors exemplified by 223, Figure 62, 232 which bears some similarities to the triazole series from Merck. Variation of the substitution of the aryl ether had little impact on PXR activation, as shown in Figure 62, with Cl-substitution (224−226) actually increasing PXR activity and fluorine (227) having no impact in this instance. The methylpyridine (228) did bring some benefit, Figure 62.…”

“…Subsequently, Vertex have disclosed their SAR against PXR for a very similar series, depicted in Figure 52. 227 Using a luciferase reporter gene assay (24 h incubation) in DPX2 cells (a human hepatoma cell line) 180 showed weaker PXR activation than 181, albeit with a similar EC 50 value, showing the chiral center has a marked impact.…”

Straightforward Synthesis of 3‐Aminothiophenes Using Activated Amides

“…This core is, indeed, a well-known bioisostere of anilines used in drug design and can be found in agrochemicals such as in dimethenamid [2] and penthiopyrad, [3] showing herbicidal and fungicidal activity respectively, and also in pharmaceuticals like the local anesthetic articaine [4] or telenzepine [5,6] which is used for the treatment of peptic ulcer (Figure 1). Moreover, according to recent studies, this scaffold is present in potent inhibitors of hepatitis C virus [7,8] and tumor growth, [9,10] as well as in anti-inflammatory [11] and anti-microbial [12] compounds.…”

Keteniminium Salts: Reactivity and Propensity toward Electrocyclization Reactions

“…The computed data showed that keteniminium salts both kinetically and thermodynamicallyundergo electrocyclization more readily than ketenes, allenes, and trienes. Besides, naphthylamines, (benzo)thiophenes, (benzo)furans and indoles are also core scaffolds for several bioactive compounds used in various areas such as agrochemicals, 26 pharmaceuticals, 27 antimitotic agents, 28 inhibitors of tubulin polymerization, 29 tumor growth, 30,31 and antiviral 32,33 compounds (Scheme 2). Our previous study has described an efficient access to 3aminobenzothiophene derivatives through the 6π-electrocyclization of the corresponding KI (Scheme 1b).…”