Finger loop inhibitors of the HCV NS5b polymerase. Part II. Optimization of tetracyclic indole-based macrocycle leading to the discovery of TMC647055

Vendeville, Sandrine; Lin, Tse‐I; Hu, Lili; Tahri, Abdellah; McGowan, David; Cummings, Maxwell D.; Amssoms, Katie; Canard, Maxime; Steen, Iris Van den; Devogelaere, Benoit; Rouan, Marie-Claude; Vijgen, Leen; Berke, Jan Martin; Dehertogh, Pascale; Fransen, Els; Cleiren, Erna; Helm, Liesbet van der; Fanning, Gregory; Emelen, Kristof Van; Nyanguile, Origène; Simmen, Kenny; Raboisson, Pierre

doi:10.1016/j.bmcl.2012.04.113

Cited by 37 publications

(26 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…100 Initial macrocyclic analogs showed enhanced potency relative to non-cyclic precursors and subsequent lead optimization of the linker, salt-bridge binder (to an acylsulfonamide), and aryl substituents led to the identification of candidate TMC647055 (Figure 7.14). 50,100,101 This 17-membered macrocyclic compound had excellent potency against the HCV GT1b replicon (EC 50 ¼ 82 nM), acceptable rat and dog PK (F ¼ 66-87%), including good liver exposure in the rat, and was shown not to result in the formation of an unstable acylglucuronide. While the compound is highly protein bound, the macrocyclization strategy achieved its goals, and TMC647055 is currently in Phase II clinical studies.…”

Section: Hcv Ns5b Polymerase Inhibitorsmentioning

confidence: 96%

“…One of these structures, containing the inhibitor 65 (Figure 7.14), formed the starting point for a macrocyclization campaign. 50,[99][100][101] Compound 65 had less than desirable physicochemical properties, some PK limitations, and a structural liability of acylglucuronide formation. The macrocyclization strategy was employed to address these issues by linking solvent exposed positions of the indole inhibitor, while maintaining and optimizing three key interaction features: a salt-bridge, the hydrophobic binding of the cyclohexyl group and the indole-aryl torsional angle of the inhibitor template.…”

Section: Hcv Ns5b Polymerase Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Linear and Macrocyclic Hepatitis C Virus Protease Inhibitors: Inhibitor Design and Macrocyclization Strategies for HCV Protease and Related Targets

Kazmierski

Jarvest

Plattner³

et al. 2014

Macrocycles in Drug Discovery

View full text Add to dashboard Cite

Enormous progress has been made towards an all-oral, very highly sustained viral response (considered a cure) treatment of hepatitis C. Key ingredients of these therapies are hepatitis C virus (HCV) protease inhibitors (PIs). The first generation linear and covalent PIs, telaprevir and boceprevir, were discovered through the enzyme substrate-based approach and are being followed by a second generation of non-covalent PIs. Many of these are macrocycles, as exemplified by the recently FDA-approved simeprevir. This chapter will detail the science successfully employed in both the substrate-based and inhibitor macrocyclization approaches. Additionally, as HCV PI C-terminal motifs develop critical contacts with the enzyme catalytic Ser139 and adjacent sites, this chapter discusses the mechanistic and structural details of such interactions for both the reversible covalent ketoamide as well as non-covalent sulfonamide and carboxylic acid moieties. Efforts to explore a cyclic boronate motif in various linear and cyclic HCV PIs in search of both Ser139-specific and opportunistic enzyme–inhibitor interactions are also summarized herein. In addition, key clinical and marketed PIs are described, including extensive references to primary literature. Finally, this chapter briefly covers key macrocyclic inhibitors of HCV RNA-dependent RNA polymerase NS5B and selected non-HCV macrocyclic protease inhibitors in order to provide additional insights into the successful design of macrocyclic drugs.

show abstract

Section: Hcv Ns5b Polymerase Inhibitorsmentioning

confidence: 96%

Section: Hcv Ns5b Polymerase Inhibitorsmentioning

confidence: 99%

Linear and Macrocyclic Hepatitis C Virus Protease Inhibitors: Inhibitor Design and Macrocyclization Strategies for HCV Protease and Related Targets

Kazmierski

Jarvest

Plattner³

et al. 2014

Macrocycles in Drug Discovery

View full text Add to dashboard Cite

show abstract

“…51 Returning attention to macrolactamization, a variation on the traditional amine-acid coupling was employed to access a series of finger loop inhibitors of hepatitis C virus (HCV) nonstructural protein 5B (NS5b) polymerase leading to the discovery of the clinical candidate TMC647055 (13, Scheme 11.2, CDI The Synthesis of Macrocycles for Drug Discovery (carbonyl diimidazole), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)) currently in Phase II trials. 52 In addition to traditional amide bond macrocyclization (indicated as an alternative in the Scheme), ring closure of the sulphonamide moiety of 11 with the aromatic carboxylic acid was employed to further rigidify the tetracyclic system. These efforts resulted in a series of polymerase inhibitors (12) from which 13 displayed an acceptable pharmacokinetic profile in dogs, including high oral bioavailability (F ¼ 87%) and systemic exposure combined with moderate plasma clearance and low volume of distribution.…”

Section: Macrolactamization and Macrolactonizationmentioning

confidence: 99%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

View full text Add to dashboard Cite

Despite the attractive nature of macrocyclic compounds for use in new pharmaceutical discovery, applications have been hindered due to the lack of appropriate synthetic methods, in particular for the construction of libraries of such molecules. However, over the last decade, a number of effective and versatile methodologies suitable for macrocyclic scaffolds have been developed and applied successfully. These include classical coupling and substitution reactions, ring-closing metathesis (RCM), cycloaddition (“click”) chemistry, multicomponent reactions (MCR), numerous organometallic-mediated processes and others. This chapter presents a comprehensive compilation of these strategies and provides examples of their use in drug discovery, along with a description of those approaches that have proven effective for the assembly of macrocyclic libraries suitable for screening.

show abstract

“…Another example of a macrocyclic HCV drug candidate has been reported with the discovery of TMC647055 (16; Figure 10.10), a potent HCV NS5B inhibitor [15]. In this case, the macrocycle was introduced in the molecule to improve the water solubility and PK characteristics of the very lipophilic 3-cyclohexylindole scaffold, resulting in a compound with better potency over the corresponding open forms and with excellent oral bioavailability.…”

Section: Interaction Of Macrocycles With Their Targetsmentioning

confidence: 99%